A constrained maximum likelihood approach to evaluate the impact of dose metric on cancer risk assessment: application to ß-chloroprene.

ß-Chloroprene (2-chloro-1,3-butadiene, CD) is used in the manufacture of polychloroprene rubber. Chronic inhalation studies have demonstrated that CD is carcinogenic in B6C3F1 mice and Fischer 344 rats. However, epidemiological studies do not provide compelling evidence for an increased risk of mortality from total cancers of the lung. Differences between the responses observed in animals and humans may be related to differences in toxicokinetics, the metabolism and detoxification of potentially active metabolites, as well as species differences in sensitivity. The purpose of this study was to develop and apply a novel method that combines the results from available physiologically based kinetic (PBK) models for chloroprene with a statistical maximum likelihood approach to test commonality of low-dose risk across species. This method allows for the combined evaluation of human and animal cancer study results to evaluate the difference between predicted risks using both external and internal dose metrics. The method applied to mouse and human CD data supports the hypothesis that a PBK-based metric reconciles the differences in mouse and human low-dose risk estimates and further suggests that, after PBK metric exposure adjustment, humans are equally or less sensitive than mice to low levels of CD exposure.

Limitations on dose estimation.

The process of estimation of dose at a target organ from the measurements of environmental concentration of potentially hazardous agents is theoretically examined. The analysis of the estimation process suggests that the design of any study which aims to find the health effects of an agent or to construct a dose-response relationship from environmental measurements must be fully scrutinized to see whether a representative dose is tractable from such measurements made on the agent or extrapolation from a set of known effects at high dose levels is feasible and desirable.

The status of indoor air pollution.

Indoor air pollution, specifically restricted in its meaning to chemicals in home indoor air environment, presents a new and probably an important challenge to the researchers of the air pollution field. The general overview of this topic suggests that the voluminous data generated in the past ten or so years have only defined the rudiments of the problem, and significant areas of research still exist. Among the important areas where information is lacking, the exposures to contaminants generated by the use of consumer products and through hobbies and crafts represent perhaps the most urgent need for substantial research.

Human occupational and nonoccupational exposure to fibers.

Human exposure to fibers in occupational and nonoccupational environments has been a health concern for nearly a century. In this review, selected results from the literature are presented to highlight the availability, limitations, and interpretive difficulties associated with the past and current human fiber exposure data sets. In the traditionally defined asbestos fibers, large amounts of the data available suffer from the diversity of sample collection and analysis methods. Two simple generalizations suggest that occupational exposures are several orders of magnitude higher than that of environmental exposures; and currently extant data and the current routine measurement practices present significant difficulties in the consistent interpretation of the data with respect to health effects. The data on the human exposures to man-made vitreous fibers are much more complete than the data on asbestos exposure, while exposure data on other man-made fibrous materials are lacking. The human exposure data to many minerals which, at times, exist in fibrous habit, are very scanty, and in view of the biological activity of some of these fibers, this lack may be of significant concern.

Lung cancer mortality in UK nickel-cadmium battery workers, 1947-2000.

AIMS: To investigate mortality from lung cancer in nickel-cadmium battery workers in relation to cumulative exposure to cadmium hydroxide. METHODS: The mortality of a cohort of 926 male workers from a factory engaged in the manufacture of nickel-cadmium batteries in the West Midlands of England was investigated for the period 1947-2000. All subjects were first employed at the plant in the period 1947-75 and employed for a minimum period of 12 months. Work histories were available for the period 1947-86; the factory closed down in 1992. Two analytical approaches were used, indirect standardisation and Poisson regression. RESULTS: Based on serial mortality rates for the general population of England and Wales, significantly increased mortality was shown for cancers of the pharynx (observed (Obs) 4, expected (Exp) 0.7, standardised mortality ratio (SMR) 559, p<0.05), non-malignant diseases of the respiratory system (Obs 61, Exp 43.0, SMR 142, p<0.05), and non-malignant diseases of the genitourinary system (Obs 10, Exp 4.1, SMR 243, p<0.05). Non-significantly increased SMRs were shown for lung cancer (Obs 45, Exp 40.7, SMR 111) and cancer of the prostate (Obs 9, Exp 7.5, SMR 116). Estimated cumulative cadmium exposures were not related to risks of lung cancer or risks of chronic obstructive pulmonary diseases, even when exposure histories were lagged first by 10, then by 20 years. CONCLUSIONS: The study findings do not support the hypotheses that cadmium compounds are human lung carcinogens.

Applications and limitations of air dispersion modeling in environmental epidemiology.

In epidemiological investigations, when the estimation of integrated exposures over long time intervals covering years or decades is required, the quantitative assignment of exposure levels by simplistic models may prove to be inadequate for most applications. This difficulty may be partially addressed by modifying the mathematical models used for the prediction of dispersions of emissions from pollution sources. A theoretical model based on the atmospheric dispersion of contaminants is proposed. While the development of the theoretical model is straightforward, the data requirements in the application of the model may impose some limitations. The methods developed to resolve or alleviate these limitations suggest that many currently used environmental exposure assignment techniques may be too crude to be of value; even the more sophisticated method proposed can only be used with some reservations. Although several difficulties associated with environmental exposure estimation remain unresolved, the careful and rigorous analysis of the available data and the application of the method suggested here can reduce the exposure misclassification errors to acceptable levels. The quantitative estimations of the limitations are based on estimation procedures and aerometric data used in a hilly terrain, and thus should represent testing of the method under an extreme condition.

Use of global positioning system technology to track subject's location during environmental exposure sampling.

Global positioning system (GPS) data recorders were worn by subjects in the Oklahoma Urban Air Toxics Study (OUATS) for automatic logging of their location as they went about their normal daily activities. The location information obtained by the GPS units had an uncertainty of about 10-20 m, which was sufficiently precise to track subjects' movements on trips outside the immediate vicinity of their homes. Due to instrument problems, primarily related to reduced battery life, the units operated for only about 30% of the total monitoring time attempted in 25 trials. The GPS data were compared to time-activity diaries kept by the subjects. In almost all cases, the GPS data confirmed all travel events reported in the subjects' diaries. Additionally, in five out of five trials in which the logging period covered most or all of the subjects' daytime activities, at least one travel event that was not recorded in the diary was detected by GPS. Notwithstanding the limitations of present technology, GPS was found to be a promising means for tracking of research subjects in community-based exposure assessment studies.

An updated meta-analysis of formaldehyde exposure and upper respiratory tract cancers.

In this study, we summarize 47 epidemiologic studies related to formaldehyde exposure and use meta-analytic techniques to assess findings for cancers of the lung, nose/nasal sinuses, and nasopharynx. Our analyses indicate that workers with formaldehyde exposure have essentially null findings for lung cancer and a slight deficit of sinonasal cancer. Nasopharyngeal cancer rates were elevated moderately in a minority of studies. Most studies, however, did not find any nasopharyngeal cancers, and many failed to report their findings. After correcting for underreporting, we found a meta relative risk of 1.0 for cohort studies. Case-control studies had a meta relative risk of 1.3. Our review of the exposure literature indicated that the nasopharyngeal cancer case-control studies represented much lower and less certain exposures than the cohort studies. We conclude that the available studies do not support a causal relation between formaldehyde exposure and nasopharyngeal cancer. This conclusion conflicts with conclusions from two previous meta-analyses, primarily because of our consideration of unreported data.

Exposure estimation in four major epidemiologic studies in the acrylonitrile industry.

The reconstruction of worker exposures has been the mainstay of modem industrial epidemiologic studies. In most cases, the researchers are faced with the difficult dilemma created by the scarcity of the exposure measurement data vis-à-vis the demands for refined quantification. The 4 industrial epidemiologic studies of workers exposed to acrylonitrile share many similarities to illustrate strengths and weaknesses of the current exposure reconstruction methodologies. The analysis of the reported exposure reconstruction methods and comparative analysis of some of the results suggest that there is a certain degree of conformity in the results of the exposure reconstruction processes in these 4 studies. At the same time, the same analysis invokes some questions with respect to the interpretation of the exposure reconstruction results.

A case-control study of lung cancer mortality in four rural Arizona smelter towns.

To investigate factors related to lung cancer mortality in four Arizona copper-smelter towns, the authors identified 142 lung cancer cases and 2 matched controls per case from decedent residents during 1979-1990. The authors obtained detailed information on lifetime residential, occupational, and smoking histories via structured telephone interviews with knowledgeable informants. The authors linked estimated historical environmental exposures to smelter emissions (based on atmospheric diffusion modeling of measured sulfur dioxide concentrations) with residential histories to derive individual profiles of residential exposure. The results of this study provided little evidence of a positive association between lung cancer and residential exposure to smelter emissions. Conditional logistic regression analysis revealed a statistically significant positive association between lung cancer and reported employment in copper mines and/or smelters, although specific factors associated with the apparently increased risk among these workers could not be identified in this community-based study.

Retrospective industrial hygiene surveys.

The true test of the long-term response of workers exposed to a hazardous agent is usually the epidemiological studies performed on same. This necessitates the long-term knowledge of exposure levels. Usually, the extent to which the exposures measured during recent experiences are representative of past exposures is difficult to assess as only limited historic measurements are available, and oftentimes the limited data are difficult to relate to today's measurement techniques. It is fallacious to assume that the conditions were worse in the past as it is fallacious to assume that they were better. The methodology of estimating past exposures to an agent based on industry-wide survey techniques is discussed.

Multicomponent error model for mass measurement based size fractionating aerosol samplers.

A mass based size fractionating aerosol sampling device such as an impactor has a number of experimental measurement errors that can affect the size distribution determination. These errors are not necessarily additive, such as weighing errors, multiplicative such as airflow errors, or a power function such as bounce. In general, the cumulative errors are a combination of different relational scales and they are likely to have different functional forms across the full range of measurements. A complete theory of errors must consider a diverse set of functional relationships between mass, flow, size distribution, and other non-linear parameters such as entry losses and bounce to estimate the error bounds for a measured size distribution and aerosol concentration. In addition, aerosol exposure measurements are single sample events. The theoretical multi-compartment error model is an extension of the Rocke and Lorenzato model of measurement errors in analytical chemistry and it includes generalized parameters for all empirically meaningful transformations. Although the general theory is complicated, heuristic reductions can be made to reduce the estimation process to a manageable size. The numerical examples of error analysis of a hypothetical impactor show that the measured distribution related error bound estimation process is not difficult to perform.

Method-induced misclassification for a respirable dust sampled using ISO/ACGIH/CEN criteria.

The single cut measurement of exposure to respirable dust is the accepted method of exposure classification in occupational hygiene. We previously showed that actual pulmonary tissue dose may be substantially different from the dose expected, or the indicated dose, based on measurements using current single cut methodologies. We now examine exposure misclassification of workers based on any single cut respirable dust measurement using the internationally accepted ISO/ACGIH/CEN single cut respirable dust measurement criteria. Hypothetical aerosols with 12 generalized size distributions typical of the method of aerosol generation (condensation, aged condensation, mechanical low energy, mechanical high energy and mixtures thereof) were assumed. Using previously reported models for sampler penetration and pulmonary deposition, Monte Carlo simulations of actual mass dose to pulmonary tissues in comparison to the dose estimate from an ideal respirable aerosol sampler were carried out. Measurement-based indicated doses were used to classify exposures into five exposure categories and these classifications were compared with the 'true' classifications from the dose-based exposure estimates. Misclassification rates were generally severe and were greatest for aerosols with mass median aerodynamic diameter (MMAD) <1 microm (approximately 100%) and MMAD 5-15 microm (65-95%). Misclassification rates were moderate (<20%) only for extremely coarse aerosols of MMAD>15 microm. Misclassification rates for oral and nasal breathing at 750 and 1500 ml tidal volume and 15 breaths/min were similar for each aerosol examined.

Design, calibration and testing of a parallel stage impactor.

The fractionation of airborne particles according to aerodynamic size by a number of impactor stages operated in parallel offers significant advantages over the commonly employed cascade impaction technique when determining mass or chemical size distribution of an aerosol. A seven stage, round jet impactor based on the parallel stage concept was designed, manufactured, calibrated and tested. The stages operate at 25 liters per minute collecting fractions of zero to 0.35, 0.70, 2.0, 4.0 and 7.0 micrometers aerodynamic diameter. The last two stages have no impaction surface and collect aerosol over the entire size range. All stages are mounted on standard 47 mm filter holders. For each stage, particles larger than the cut-off size impact on a thick adhesive surface and are discarded while those smaller are collected on a filter. The ratio of the particle mass penetrating to the filter of a given stage to the mass of the entire aerosol represents the cumulative mass fraction associated with the cut-off diameter for that stage. Any losses associated with non-ideal behavior in the impactor become an inherent part of the calibration. Calibration of the impactor showed that stage cut-off sizes are close to the values predicted by impactor theory. A novel technique employing polydisperse aerosol was used in the calibration. Challenge of the impactor calibration with solid aerosols of known size distribution gave excellent results. Tests for particle bounce after four hours of operation in urban aerosol showed that accumulation of particles at the impaction surface does not increase bounce or blow-off. Microscopic examination of impaction surfaces immediately after sampling showed most of the particles to be embedded within the adhesive rather than on the surface.

Distortion of cascade impactor measured size distribution due to bounce and blow-off.

Accurate measurement of particle size distribution by a cascade impactor requires that particles remain on the collection surfaces after impaction. Recent studies show that, when a solid aerosol is sampled, significant rebound and re-entrainment of particles occur in cascade impactors. A mathematical model of a cascade impactor including collection efficiency functions for solid aerosols on various impaction surfaces was developed and used to operate upon a series of log-normal size distributions. The impactor modeled was a six stage Andersen operated at 28.3 L/min. When bare metal or glass impaction surfaces are used, the impactor indicates non-log-normal distributions and the estimated distribution parameters are in error by as much as a factor of 7. When glass fiber impaction surfaces are used, although less serious errors are indicated, the deviation from log-normality is significant for aerosols with MMD larger than 3 micrometers. When oil covered impaction stages are used the indicated distributions parameters are acceptably close to the input parameters. The accuracy of the model was verified experimentally.

The inertial behavior of fibers.

The inertial deposition is given considerable credit in the deposition of inhaled particulate matter in the upper respiratory tract. A determination of the parameters governing the impaction of fibers must be the basis of evaluating the role of impaction in the respirability of fibrous dusts. The study reported here describes an experimental method of defining the inertial behavior of fibers. The results of the experiments show that the aspect ratio of the fibers plays a much more important role than hitherto considered. The results of the experimental work gave an empirical mathematical model for the prediction of the impaction of fibers from the physical properties of fibers such as density, fiber diameters and aspect ratio. In addition an equivalent diameter based on inertial properties of the fiber is developed.

Airborne fiber concentrations during splitting open and boxing bags of asbestos.

Measured airborne concentrations of asbestos are often unavailable to assess different epidemiologic estimates of past personal exposure levels or concentrations near specific operations involving handling asbestos. The purpose of this study was to assess the potential use of a laboratory study in estimating exposure to asbestos in operations that ceased for many years. The asbestos transfer operations were simulated by splitting and boxing 4.5-kg paper bags of chrysotile asbestos in an enclosed chamber ventilated at 28.2 air changes per hour (ACH). Two recirculation fans achieved chamber air mixing. The airborne concentration of asbestos fibers was determined by sampling air through membrane filters at a rate of 10 l/min and by analysing fibers by phase contrast optical microscopy to determine 15-min average airborne concentrations. Samplers were located at four equidistant locations from the operation. Opening a maximum of seven bags in 15 min was associated with an asbestos-in-air concentration of less than 2 x 10(-6) fibers/m3 (f/m3) in splitting open and boxing and less than 0.85 x 10(-6) f/m3 in boxing of pre-split bags. The measured airborne asbestos concentration exhibited a linear trend with the number of bags opened per 15 min. The empirical results were utilised to model fiber concentrations for various ventilation rates. It was concluded that the distribution of the operation within the workday and the ventilation rate are the two most important variables in the determination of the estimated time-weighted average concentration. Splitting open and boxing 32 bags of asbestos over an 8-h period at a rate of 4 bags/h over an 8-h period results in a calculated time-weighted average exposure of about 1 x 10(-6) f/m3 in a work space with 20 ACH and approximately 7 x 10(-6) f/m3 in a work space with 2 ACH. Splitting open and boxing at a rate of 12 bags/h for 2 h and 45 min yielded calculated concentrations less than one-half of the above mentioned values. These results should serve as a useful benchmark for epidemiologists concerned with the magnitude of exposure in historically dusty industrial tasks.