Arch I. Carson

Workshop summary: Phosgene-induced pulmonary toxicity revisited: Appraisal of early and late markers of pulmonary injury from animal models with emphasis on human significance

A workshop was held February 14, 2007, in Arlington, VA, under the auspices of the Phosgene Panel of the American Chemistry Council. The objective of this workshop was to convene inhalation toxicologists and medical experts from academia, industry and regulatory authorities to critically discuss past and recent inhalation studies of phosgene in controlled animal models. This included presentations addressing the benefits and limitations of rodent (mice, rats) and nonrodent (dogs) species to study concentration × time (C × t) relationships of acute and chronic types of pulmonary changes. Toxicological endpoints focused on the primary pulmonary effects associated with the acute inhalation exposure to phosgene gas and responses secondary to injury. A consensus was reached that the phosgene-induced increased pulmonary extravasation of fluid and protein can suitably be probed by bronchoalveolar lavage (BAL) techniques. BAL fluid analyses rank among the most sensitive methods to detect phosgene-induced noncardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum protein concentrations in BAL fluid occurred within 1 day after exposure, typically followed by a latency period up to about 15 h, which is reciprocal to the C × t exposure relationship. The C × t relationship was constant over a wide range of concentrations and single exposure durations. Following intermittent, repeated exposures of fixed duration, increased tolerance to recurrent exposures occurred. For such exposure regimens, chronic effects appear to be clearly dependent on the concentration rather than the cumulative concentration × time relationship. The threshold C × t product based on an increased BAL fluid protein following single exposure was essentially identical to the respective C × t product following subchronic exposure of rats based on increased pulmonary collagen and influx of inflammatory cells. Thus, the chronic outcome appears to be contingent upon the acute pulmonary threshold dose. Exposure concentrations high enough to elicit an increased acute extravasation of plasma constituents into the alveolus may also be associated with surfactant dysfunction, intra-alveolar accumulation of fibrin and collagen, and increased recruitment and activation of inflammatory cells. Although the exact mechanisms of toxicity have not yet been completely elucidated, consensus was reached that the acute pulmonary toxicity of phosgene gas is consistent with a simple, irritant mode of action at the site of its initial deposition/retention. The acute concentration × time mortality relationship of phosgene gas in rats is extremely steep, which is typical for a local, directly acting pulmonary irritant gas. Due to the high lipophilicity of phosgene gas, it efficiently penetrates the lower respiratory tract. Indeed, more recent published evidence from animals or humans has not revealed appreciable irritant responses in central and upper airways, unless exposure was to almost lethal concentrations. The comparison of acute inhalation studies in rats and dogs with focus on changes in BAL fluid constituents demonstrates that dogs are approximately three to four times less susceptible to phosgene than rats under methodologically similar conditions. There are data to suggest that the dog may be useful particularly for the study of mechanisms associated with the acute extravasation of plasma constituents because of its size and general morphology and physiology of the lung as well as its oronasal breathing patterns. However, the study of the long-term sequelae of acute effects is experimentally markedly more demanding in dogs as compared to rats, precluding the dog model to be applied on a routine base. The striking similarity of threshold concentrations from single exposure (increased protein in BAL fluid) and repeated-exposure 3-mo inhalation studies (increased pulmonary collagen deposition) in rats supports the notion that chronic changes depend on acute threshold mechanisms.

Spirometry in the Occupational Setting

: This position statement reviews several aspects of spirometric testing in the workplace, where spirometry is employed in the primary, secondary, and tertiary prevention of occupational lung disease. Primary prevention includes pre-placement and fitness-for-duty examinations as well as research and monitoring of health status in groups of exposed workers; secondary prevention includes periodic medical screening of individual workers for early effects of exposure to known occupational hazards; and tertiary prevention includes clinical evaluation and impairment/disability assessment. For all of these purposes, valid spirometry measurements are critical, requiring: documented spirometer accuracy and precision, a rigorous and standardized testing technique, standardized measurement of pulmonary function values from the spirogram, adequate initial and refresher training of spirometry technicians, and, ideally, quality assessment of samples of spirograms. Interpretation of spirometric results usually includes comparison with predicted values and should also evaluate changes in lung function over time. Response to inhaled bronchodilators and changes in relation to workplace exposure may also be assessed. Each of these interpretations should begin with an assessment of test quality and, based on the most recent ATS recommendations, should rely on a few reproducible indices of pulmonary function (FEV1, FVC, and FEV1/FVC.) The use of FEF rates (e.g., the FEF25-75%) in interpreting results for individuals is strongly discouraged except when confirming borderline airways obstruction. Finally, the use of serial PEF measurements is emerging as a method for confirming associations between reduced or variable pulmonary function and workplace exposures in the diagnosis of occupational asthma. Throughout this position statement, ACOEM makes detailed recommendations to ensure that each of these areas of test performance and interpretation follow current recommendations/standards in the pulmonary and regulatory fields. Submitted by the Occupational and Environmental Lung Disorder Committee on November 16,1999. Approved by the ACOEM Board of Directors on January 4,2000.

Determination of urinary mandelic and phenylglyoxylic acids in styrene exposed workers and a control population

Styrene is rapidly metabolized in humans to mandelic () and phenylglyoxylic acids (P) which are excreted in urine. The present study investigates a gas chromatographic technique for measuring urinary concentrations of MA and PGA of workers exposed to styrene, compares the urinary concentrations of metabolites with time-weighted average air exposures to styrene and determines the levels of these metabolites in a population of workers not exposed to styrene. Post-shift urine specimens were obtained from a group of workers exposed to styrene in the reinforced plastic industry and from a control group. High positive correlation was found between post-shift urinary concentrations of metabolites and 8-hour TWA styrene exposure. Both MA and total metabolites (MA + PGA) gave correlation coefficient values of 0.96, p less than 0.0001. The mean MA excretion for the control groups was 6 mg/L. Determination of the concentration of these metabolites in a post-shift urine provides an effective means of estimating and monitoring human exposure to styrene.

Validation of an asthma questionnaire for use in healthcare workers.

Background: Previous studies have described increased occurrence of asthma among healthcare workers, but to our knowledge there are no validated survey questionnaires with which to study this occupational group. Aims: To develop, validate, and refine a new survey instrument on asthma for use in epidemiological studies of healthcare workers. Methods: An initial draft questionnaire, designed by a multidisciplinary team, used previously validated questions where possible; the occupational exposure section was developed by updating health services specific chemical lists through hospital walk-through surveys and review of material safety data sheets. A cross-sectional validation study was conducted in 118 non-smoking subjects, who also underwent bronchial challenge testing, an interview with an industrial hygienist, and measurement of specific IgE antibodies to common aeroallergens. Results: The final version consisted of 43 main questions in four sections. Time to completion of the questionnaire ranged from 13 to 25 minutes. Test–retest reliability of asthma and allergy items ranged from 75% to 94%, and internal consistency for these items was excellent (Cronbach’s α ⩾ 0.86). Against methacholine challenge, an eight item combination of asthma related symptoms had a sensitivity of 71% and specificity of 70%; against a physician diagnosis of asthma, this same combination showed a sensitivity of 79% and specificity of 98%. Agreement between self-reported exposures and industrial hygienist review was similar to previous studies and only moderate, indicating the need to incorporate more reliable methods of exposure assessment. Against the aerollergen panel, the best combinations of sensitivity and specificity were obtained for a history of allergies to dust, dust mite, and animals. Conclusions: Initial evaluation of this new questionnaire indicates good validity and reliability, and further field testing and cross-validation in a larger healthcare worker population is in progress. The need for development of more reliable occupational exposure assessment methods that go beyond self-report is underscored.

Statistical methods for describing occupational exposure measurements.

An important step in studies relating worker health to industrial exposure is the estimation of mean exposure levels. The investigator frequently has to rely on industrial hygiene measurements collected for other purposes. Samples may have been taken at several companies on different dates, and on each occasion multiple individual samplers may have been employed. Often it is not recognized that readings from such a hierarchical arrangement are correlated; for example, samples taken at the same time and location are more alike than samples taken on different days. This correlation invalidates the commonly used standard errors of sample means and the usual sample standard deviation. A component of variance analysis is suggested which quantifies within-day, between-day and between-company variation. Estimators of mean exposure are presented with correct standard errors. The techniques are illustrated by a small set of data and by a recent study of exposures to styrene in 36 companies manufacturing reinforced plastics.

Occupational styrene exposure for twelve product categories in the reinforced-plastics industry.

Approximately 1500 occupational styrene exposure values from 28 reinforced-plastic manufacturers were collected retrospectively from companies and state and federal agencies. This report describes the major types of manufacturing processes within the reinforced-plastics industry and reports on the availability, collection and analysis of historical exposure information. Average exposure to styrene in most open-mold companies (24-82 ppm) was generally 2-3 times the exposure in press-mold companies (11-26 ppm). Manufacturers of smaller boats had mean styrene exposures of 82 ppm as compared to 37 ppm for yacht companies. There was considerable overlap in styrene exposure among job titles classified as directly exposed within open- and press-mold processing.

A global survey of occupational health competencies and curriculum.

Abstract The World Health Organization has identified a world-wide shortage of occupational health professionals, but evidence suggests that the work and education of these professionals vary across countries. This survey examined the professionaldeveloprnent of occupational physicians, occupational nurses, industriaL hygienists, and ergonomists in terms of practice competencies and academic curriculum. Of 89 countries that received the survey, 48 (54%) responded. Important differences in competencies and curricula were identified for all groups. More competencies were identified more frequently in deyeloped countries. Academic programs existed more often in developed countries, but curriculum contentsvaried. The study provides a concrete reference point for discussion and developtnentof competencies and curriculum.

Pulmonary function changes in Chinese hamsters exposed six months to diesel exhaust

Chinese hamsters were exposed for eight hours per day to automotive diesel exhaust emissions which were diluted with air (18 to 1) and had a particulate level of 6.4 mg/m3. Pulmonary function measurements were made after six months exposure. Body weight (BW), lung weight (LW), vital capacity (VC), residual volume by water displacement (RVw) and by gas dilution (RVD), alveolar volume (VA), and carbon monoxide transfer factor (DLCO) were measured. LW showed a significant increase in the diesel exposed animals (P < 0.01) while VC, RVW, and DLCO showed decreases (P < 0.01). Static deflation volume-pressure curves showed depressed deflation volumes for diesel exposed animals when volumes were corrected for body weight and even greater depressed volumes when volumes were corrected for lung weight. However, when volumes were expressed as percent vital capacity, the diesel exposed animals had higher lung volumes at 0 and 5 cm H2O. Results of the pathological examination of the lung tissue will be necessary for final analysis of our findings. However, preliminary interpretation indicates possible emphysematous changes which are compatible with the observed decrease in DLCO.

Assessing postdisaster psychological stress in hazardous waste operations and emergency response (HAZWOPER) workers

OBJECTIVE To assess the prevalence of traumatic stress experienced by secondary responders to disaster events to determine if mental health education should be included in HAZWOPER training. METHODS Preexisting survey tools for assessing posttraumatic stress disorder (PTSD), resiliency, and mental distress were combined to form a web-based survey tool that was distributed to individuals functioning in secondary response roles. Data were analyzed using the Fisher exact test, 1-way ANOVA, and 1-sample t tests. RESULTS Respondents reported elevated PTSD levels (32.9%) as compared to the general population. HAZWOPER-trained responders with disaster work experience were more likely to be classified as PTSD positive as compared to untrained, inexperienced responders and those possessing only training or experience. A majority (68.75%) scored below the mean resiliency level of 80.4 on the Connor-Davidson Resilience Scale. Respondents with only training or both training and experience were more likely to exhibit lower resiliency scores than those with no training or experience. PTSD positivity correlated with disaster experience. Among respondents, 91% indicated support for mental health education. CONCLUSIONS Given the results of the survey, consideration should be given to the inclusion of pre- and postdeployment mental health education in the HAZWOPER training regimen.