Randall J. Smith

A dose-response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure.

We performed a quantitative assessment of the risk of lung cancer from exposure to cadmium based on a retrospective cohort mortality study of cadmium-exposed workers. The study population consisted of white male workers who were employed for at least 6 months at a cadmium smelter between January 1, 1940, and December 31, 1969, and who were first employed at the facility on or after January 1, 1926. The study findings were analyzed using a modified life-table analysis to estimate standardized mortality ratios (SMRs), and various functional forms (i.e., exponential, power, additive relative rate, and linear) of Poisson and Cox proportional hazards models to examine the dose-response relationship. Estimates of working lifetime risk (45 years) were developed using an approach that corrects for competing causes of death. An excess in mortality from lung cancer was observed for the entire cohort (SMR = 149, 95% confidence interval (CI) = 95, 222). Mortality from lung cancer was greatest among non-Hispanic workers (SMR = 211, 95% CI = 131, 323), among workers in the highest cadmium exposure group (SMR = 272, 95% CI = 123, 513), and among workers with 20 or more years since the first exposure (SMR = 161, 95% CI = 100, 248). A statistically significant dose-response relationship was evident in nearly all of the regression models evaluated. Based on our analyses, the lifetime excess lung cancer risk at the current Occupational Safety and Health Administration standard for cadmium fumes of 100 micrograms/m3 is approximately 50 to 111 lung cancer deaths per 1000 workers exposed to cadmium for 45 years.

Exposure-response analysis of risk of respiratory disease associated with occupational exposure to chrysotile asbestos.

OBJECTIVES: To evaluate alternative models and estimate risk of mortality from lung cancer and asbestosis after occupational exposure to chrysotile asbestos. METHODS: Data were used from a recent update of a cohort mortality study of workers in a South Carolina textile factory. Alternative exposure-response models were evaluated with Poisson regression. A model designed to evaluate evidence of a threshold response was also fitted. Lifetime risks of lung cancer and asbestosis were estimated with an actuarial approach that accounts for competing causes of death. RESULTS: A highly significant exposure-response relation was found for both lung cancer and asbestosis. The exposure-response relation for lung cancer seemed to be linear on a multiplicative scale, which is consistent with previous analyses of lung cancer and exposure to asbestos. In contrast, the exposure-response relation for asbestosis seemed to be nonlinear on a multiplicative scale in this analysis. There was no significant evidence for a threshold in models of either the lung cancer or asbestosis. The excess lifetime risk for white men exposed for 45 years at the recently revised OSHA standard of 0.1 fibre/ml was predicted to be about 5/1000 for lung cancer, and 2/1000 for asbestosis. CONCLUSIONS: This study confirms the findings from previous investigations of a strong exposure-response relation between exposure to chrysotile asbestos and mortality from lung cancer, and asbestosis. The risk estimates for lung cancer derived from this analysis are higher than those derived from other populations exposed to chrysotile asbestos. Possible reasons for this discrepancy are discussed.

Lung Cancer Risk and Workplace Exposure to Environmental Tobacco Smoke

OBJECTIVES We sought to quantitatively evaluate the association between work-place environmental tobacco smoke exposure and lung cancer. METHODS We performed a meta-analysis in 2003 of data from 22 studies from multiple locations worldwide of workplace environmental tobacco smoke exposure and lung cancer risk. Estimates of relative risk from these studies were analyzed by fitting the data to fixed and mixed effects models. Analyses of highly exposed workers and of the relationship between duration of exposure and lung cancer were also performed. RESULTS The meta-analysis indicated a 24% increase in lung cancer risk (relative risk [RR]=1.24; 95% confidence interval [CI]=1.18, 1.29) among workers exposed to environmental tobacco smoke. A 2-fold increased risk (RR=2.01; 95% CI=1.33, 2.60) was observed for workers classified as being highly exposed to environmental tobacco smoke. A strong relationship was observed between lung cancer and duration of exposure to environmental tobacco smoke. CONCLUSIONS The findings from this investigation provide the strongest evidence to date that exposure to environmental tobacco smoke in the workplace is associated with an increased risk of lung cancer.

Predicted Lung Cancer Risk Among Miners Exposed to Diesel Exhaust Particles

Several quantitative risk assessment models have been published for occupational and environmental exposures to diesel exhaust particles (DEP). These risk assessment models are reviewed and applied to predict lung cancer for miners exposed to DEP. The toxicologically based unit risk estimates varied widely (from 2 to 220 x 10(-6) per micrograms/m3). The epidemiologically based unit risk estimates were less variable and suggest higher risks (from 100 to 920 x 10(-6) per micrograms/m3). The wide range of risk estimates derived from these analyses reflects the strong assumptions and large uncertainties underlying these models. All of the models suggest relatively high risks (i.e., > 1/1,000) for miners with long-term exposures greater than 1,000 micrograms/m3. This is not surprising, given the fact that miners may be exposed to DEP concentrations similar to those that induced lung cancer in rats and mice, and substantially higher that the exposure concentrations in the positive epidemiologic studies.

Contributions of dust exposure and cigarette smoking to emphysema severity in coal miners in the United States

RATIONALE Previous studies have shown associations between dust exposure or lung burden and emphysema in coal miners, although the separate contributions of various predictors have not been clearly demonstrated. OBJECTIVES To quantitatively evaluate the relationship between cumulative exposure to respirable coal mine dust, cigarette smoking, and other factors on emphysema severity. METHODS The study group included 722 autopsied coal miners and nonminers in the United States. Data on work history, smoking, race, and age at death were obtained from medical records and questionnaire completed by next-of-kin. Emphysema was classified and graded using a standardized schema. Job-specific mean concentrations of respirable coal mine dust were matched with work histories to estimate cumulative exposure. Relationships between various metrics of dust exposure (including cumulative exposure and lung dust burden) and emphysema severity were investigated in weighted least squares regression models. MEASUREMENTS AND MAIN RESULTS Emphysema severity was significantly elevated in coal miners compared with nonminers among ever- and never-smokers (P < 0.0001). Cumulative exposure to respirable coal mine dust or coal dust retained in the lungs were significant predictors of emphysema severity (P < 0.0001) after accounting for cigarette smoking, age at death, and race. The contributions of coal mine dust exposure and cigarette smoking were similar in predicting emphysema severity averaged over this cohort. CONCLUSIONS Coal dust exposure, cigarette smoking, age, and race are significant and additive predictors of emphysema severity in this study.

Exposure to crystalline silica, silicosis, and lung disease other than cancer in diatomaceous earth industry workers: a quantitative risk assessment.

Objectives: To estimate excess lifetime risk of (a) mortality from lung disease other than cancer (LDOC), and, (b) onset of radiographic silicosis, arising from occupational exposure to respirable crystalline silica dust. Methods: Data from a cohort of California diatomaceous earth mining and processing workers exposed to crystalline silica dust (mainly as cristobalite) were reanalyzed with Poisson regression methods with internal and external adjustments for potential confounding by calendar time, age, smoking, Hispanic ethnicity, and time since first observation. Model fit was evaluated by comparing deviances and fitting cubic spline models. Lifetime risks of death from LDOC and radiographic silicosis were estimated up to age 85 with an actuarial approach accounting for competing causes of death. Results: For deaths due to LDOC, a linear relative rate model gave the best fit in Poisson regression analyses. At the mean cumulative exposure of LDOC cases to silica, after adjustment for smoking, the estimated rate ratio was 4.2 (p<0.0001); at the maximum cumulative exposure of cases, the rate ratio was 18.4. The excess lifetime risk for white men exposed to respirable cristobalite dust for 45 years at the current permissible exposure limit (PEL; about 0.05 mg/m3) of the Occupational Safety and Health Administration was 54/1000 (95% confidence interval (95% CI) 17 to 150). For 70 incident cases of radiographic silicosis largely manifest before the end of employment, the best fit was also the linear relative rate model, predicting a rate ratio of 25.6 for silicosis at the mean cumulative exposure of the cases (p<0.0001). The excess lifetime risk for silicosis at the current PEL was 75/1000. Conclusion: Current occupational health standards for crystalline silica permit risks of lung disease other than cancer far in excess of what is usually considered acceptable by the Occupational Safety and Health Administration (a lifetime risk of less than one in a thousand deaths).

Teratogenicity of 2-Ethoxxethanol by Dermal Application

ABSTRACTUndiluted 2-ethoxyethanol or water (control) was applied to the skin of pregnant Sprague-Dawley rats on days 7–16 of gestation (sperm = day 1). Applications were made 4 times daily in volumes of 0.25 or 0.50 ml 2-ethoxyethanol. Females exhibited ataxia following treatment of the high-dose group, and weight gain was significantly (p<0.001) reduced in the last half of gestation. Litters were collected by caesarian section on day 21 of gestation, and fetuses were examined for external defects. Half of the fetuses were cleared and stained in alizarin red S for skeletal examinations, and half were examined for visceral defects by the Wilson technique. Intrauterine death was 100% in the high-dose group. In the lower dosage group, there was a significant increase in the number of pregnant females with 100% dead implants (p<0.001), a significant reduction in the number of live fetuses per litter (p<0.001), a significant reduction in fetal body weight (p<0.001), and a significant increase in the incidence ...

Development of a fibre size-specific job-exposure matrix for airborne asbestos fibres.

Objective: To develop a method for estimating fibre size-specific exposures to airborne asbestos dust for use in epidemiological investigations of exposure-response relations. Methods: Archived membrane filter samples collected at a Charleston, South Carolina asbestos textile plant during 1964–8 were analysed by transmission electron microscopy (TEM) to determine the bivariate diameter/length distribution of airborne fibres by plant operation. The protocol used for these analyses was based on the direct transfer method published by the International Standards Organization (ISO), modified to enhance fibre size determinations, especially for long fibres. Procedures to adjust standard phase contrast microscopy (PCM) fibre concentration measures using the TEM data in a job-exposure matrix (JEM) were developed in order to estimate fibre size-specific exposures. Results: A total of 84 airborne dust samples were used to measure diameter and length for over 18 000 fibres or fibre bundles. Consistent with previous studies, a small proportion of airborne fibres were longer than >5 μm in length, but the proportion varied considerably by plant operation (range 6.9% to 20.8%). The bivariate diameter/length distribution of airborne fibres was expressed as the proportion of fibres in 20 size-specific cells and this distribution demonstrated a relatively high degree of variability by plant operation. PCM adjustment factors also varied substantially across plant operations. Conclusions: These data provide new information concerning the airborne fibre characteristics for a previously studied textile facility. The TEM data demonstrate that the vast majority of airborne fibres inhaled by the workers were shorter than 5 μm in length, and thus not included in the PCM-based fibre counts. The TEM data were used to develop a new fibre size-specific JEM for use in an updated cohort mortality study to investigate the role of fibre dimension in the development of asbestos-related lung diseases.

Pulmonary inflammation and crystalline silica in respirable coal mine dust: dose-response

This study describes the quantitative relationships between early pulmonary responses and the estimated lungburden or cumulative exposure of respirable-quartz or coal mine dust. Data from a previous bronchoalveolar lavage (BAL) study in coal miners (n = 20) and nonminers (n = 16) were used including cell counts of alveolar macrophages AMs) and polymorphonuclear leukocytes (PMNs), and the antioxidant superoxide dismutase (SOD) levels. Miners’ individual working lifetime particulate exposures were estimated from work histories and mine air sampling data, and quartz lung-burdens were estimated using a lung dosimetry model. Results show that quartz, as either cumulative exposure or estimated lung-burden, was a highly statistically significant predictor of PMN response (P< 00001); however cumulative coal dust exposure did not significantly add to the prediction of PMNs (P = 0.2) above that predicted by cumulative quartz exposure (P < 0.0001). Despite the small study size, radiographic category was also significantly related to increasing levels of both PMNs and quartz lung burden (P-values < 0.04). SOD in BAL fluid rose linearly with quartz lung burden (P < 0.01), but AM count in BAL fluid did not (P > 0.4). This study demonstrates dose-response relationships between respirable crystalline silica in coal mine dust and pulmonary inflammation, antioxidant production, and radiographic small opacities.

Selecting an exposure lag period.

In epidemiology, there is an inclination to consider more credible the larger estimates of exposure effect. For example, higher relative risks or rate ratios are often emphasized as a criterion for choosing among various hypothesized exposurelag values. An alternative criterion for this choice might be based on a goodness-of-fit measure. We present examples, based on hypothetical data, in which an exposure-lag parameter is estimated by trial and error fitting: we compare the behavior of the likelihood-ratio goodness-of-fit statistic obtained over the assigned values of the parameter with that of the relative risk. We show that there can be inconsistencies between the highest-estimate and likelihood-based goodness-of-fit criteria. Concern about the validity of the highest-estimate criterion prompts us to recommend that this criterion not be used for the estimation of exposure-weighting parameters, which should preferably be based on a priori biological knowledge or on goodness-of-fit criteria.