First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials.

BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

Challenges and Opportunities for Occupational Epidemiology in the Twenty-first Century.

PURPOSE OF REVIEW: There are many opportunities and challenges for conducting occupational epidemiologic studies today. In this paper, we summarize the discussion of a symposium held at the Epidemiology in Occupational Health (EPICOH) conference, Chicago 2014, on challenges for occupational epidemiology in the twenty-first century. RECENT FINDINGS: The increasing number of publications and attendance at our conferences suggests that worldwide interest in occupational epidemiology has been growing. There are clearly abundant opportunities for new research in occupational epidemiology. Areas ripe for further work include developing improved methods for exposure assessment, statistical analysis, studying migrant workers and other vulnerable populations, the use of biomarkers, and new hazards. Several major challenges are also discussed such as the rapidly changing nature and location of work, lack of funding, and political/legal conflicts. As long as work exists there will be occupational diseases that demand our attention, and a need for epidemiologic studies designed to characterize these risks and to support the development of preventive strategies. Despite the challenges and given the important past contribution in this field, we are optimistic about the importance and continued vitality of the research field of occupational epidemiology.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Results from a Ukrainian-US collaborative study: prevalence and predictors of respiratory symptoms among Ukrainian coal miners.

BACKGROUND: Underground coal mining is an expanding industry in Ukraine, yet little is known about the burden of respiratory disease among Ukrainian miners. METHODS: A Fogarty International Center-supported collaboration between researchers at the University of Illinois and the Institute of Occupational Health in Kyiv, Ukraine formed to improve capacity for conducting and monitoring medical surveillance among Ukrainian coal miners. A cross-sectional survey among a random sample of working and former miners was conducted; demographic, work, and health information were collected using a standardized questionnaire. Weighted prevalence rates were calculated and predictors of respiratory symptoms explored. RESULTS: Improvements in infrastructure, including spirometry and chest radiography testing, transformed medical surveillance among these miners. Results from the health study included that the prevalence of respiratory symptoms was higher among former compared to current miners (shortness of breath 35.6% vs. 5.1%; chronic bronchitis 18.1% vs. 13.9%, respectively). A statistically significant exposure-response relationship was observed between years mining and respiratory symptoms in former miners and between years mining at the coal face and respiratory symptoms among current miners. Evidence of downward bias from the healthy worker survivor effect was observed. CONCLUSIONS: This successful international collaboration built a sustainable infrastructure for conducting workplace medical surveillance and research. The resulting study was the first in the western literature to report on respiratory symptoms in this population; likely underestimation of disease rates due to selection and measurement biases was demonstrated. Efforts should continue to build this collaboration and to characterize and reduce respiratory illness among Ukrainian coal miners.

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours.

BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.

An epidemiological study of the role of chrysotile asbestos fibre dimensions in determining respiratory disease risk in exposed workers.

BACKGROUND: Evidence from toxicological studies indicates that the risk of respiratory diseases varies with asbestos fibre length and width. However, there is a total lack of epidemiological evidence concerning this question. METHODS: Data were obtained from a cohort mortality study of 3072 workers from an asbestos textile plant which was recently updated for vital status through 2001. A previously developed job exposure matrix based on phase contrast microscopy (PCM) was modified to provide fibre size-specific exposure estimates using data from a re-analysis of samples by transmission electron microscopy (TEM). Cox proportional hazards models were fit using alternative exposure metrics for single and multiple combinations of fibre length and diameter. RESULTS: TEM-based cumulative exposure estimates were found to provide stronger predictions of asbestosis and lung cancer mortality than PCM-based estimates. Cumulative exposures based on individual fibre size-specific categories were all found to be highly statistically significant predictors of lung cancer and asbestosis. Both lung cancer and asbestosis were most strongly associated with exposure to thin fibres (<0.25 microm). Longer (>10 microm) fibres were found to be the strongest predictors of lung cancer, but an inconsistent pattern with fibre length was observed for asbestosis. Cumulative exposures were highly correlated across all fibre size categories in this cohort (0.28-0.99, p values <0.001), which complicates the interpretation of the study findings. CONCLUSIONS: Asbestos fibre dimension appears to be an important determinant of respiratory disease risk. Current PCM-based methods may underestimate asbestos exposures to the thinnest fibres, which were the strongest predictor of lung cancer or asbestosis mortality in this study. Additional studies are needed of other asbestos cohorts to further elucidate the role of fibre dimension and type.

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 microm 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 mum 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.

Mortality among a cohort of garment workers exposed to formaldehyde: an update.

AIMS: To evaluate the mortality experience of 11 039 workers exposed to formaldehyde for three months or more in three garment plants. The mean time weighted average formaldehyde exposure at the plants in the early 1980s was 0.15 ppm but past exposures may have been substantially higher. METHODS: Vital status was updated through 1998, and life table analyses were conducted. RESULTS: Mortality from all causes (2206 deaths, standardised mortality ratio (SMR) 0.92, 95% CI 0.88 to 0.96) and all cancers (SMR 0.89, 95% CI 0.82 to 0.97) was less than expected based on US mortality rates. A non-significant increase in mortality from myeloid leukaemia (15 deaths, SMR 1.44, 95% CI 0.80 to 2.37) was observed. Mortality from myeloid leukaemia was greatest among workers first exposed in the earliest years when exposures were presumably higher, among workers with 10 or more years of exposure, and among workers with 20 or more years since first exposure. No nasal or nasopharyngeal cancers were observed. Mortality from trachea, bronchus, and lung cancer (147 deaths, SMR 0.98, 95% CI 0.82 to 1.15) was not increased. Multiple cause mortality from leukaemia was increased almost twofold among workers with both 10 or more years of exposure and 20 years or more since first exposure (15 deaths, SMR 1.92, 95% CI 1.08 to 3.17). Multiple cause mortality from myeloid leukaemia among this group of workers was also significantly increased (8 deaths, SMR 2.55, 95% CI 1.10 to 5.03). CONCLUSIONS: Results support a possible relation between formaldehyde exposure and myeloid leukaemia mortality. Previous epidemiological studies supporting a relation between formaldehyde exposure and leukaemia mortality have been primarily of formaldehyde exposed professional groups, not formaldehyde exposed industrial workers. Limitations include limited power to detect an excess for rare cancers such as nasal and nasopharyngeal cancers and lack of individual exposure estimates.

Mortality analyses in a cohort of 18 235 ethylene oxide exposed workers: follow up extended from 1987 to 1998.

AIMS: To extend mortality follow up from 1987 to 1998 for cohort of 18 235 men and women exposed to ethylene oxide. METHODS: Standard mortality follow up, life table and Cox regression analysis. RESULTS: There were 2852 deaths, compared with 1177 in the earlier 1987 follow up. There was no overall excess of haematopoietic cancers combined or of non-Hodgkin's lymphoma. However, internal exposure-response analyses found positive trends for haematopoietic cancers which were limited to males (15 year lag). The trend in haematopoietic cancer was driven by lymphoid tumours (non-Hodgkin's lymphoma, myeloma, lymphocytic leukaemia), which also have a positive trend with cumulative exposure for males with a 15 year lag. Haematopoietic cancer trends were somewhat weaker in this analysis than trends in the earlier follow up, and analyses restricted to the post-1987 data did not show any significant positive trends (exposure levels dropped sharply in the early 1980s). Breast cancer did not show any overall excess, although there was an excess in the highest cumulative exposure quartile using a 20 year lag. Internal exposure-response analyses found positive trend for breast cancer using the log of cumulative exposure with a 20 year lag. CONCLUSIONS: There was little evidence of any excess cancer mortality for the cohort as a whole, with the exception of bone cancer based on small numbers. Positive exposure-response trends for lymphoid tumours were found for males only. Reasons for the sex specificity of this effect are not known. There was also some evidence of a positive exposure-response for breast cancer mortality.

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/m(3)) 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).

Pooled exposure-response analyses and risk assessment for lung cancer in 10 cohorts of silica-exposed workers: an IARC multicentre study.

OBJECTIVES: Silica is one of the most common occupational exposures worldwide. In 1997 the International Agency for Research on Cancer (IARC) classified inhaled crystalline silica as a human carcinogen (group 1), but acknowledged limitations in the epidemiologic data, including inconsistencies across studies and the lack of extensive exposure-response data. We have conducted a pooled exposure-response analysis of 10 silica-exposed cohorts to investigate lung cancer. METHODS: The pooled cohort included 65,980 workers (44,160 miners, 21,820 nominees), and 1,072 lung cancer deaths (663 miners, 409 nonminers). Follow-up has been extended for five of these cohorts beyond published data. Quantitative exposure estimates by job and calendar time were adopted, modified, or developed to permit common analyses by respirable silica (mg/m3) across cohorts. RESULTS: The log of cumulative exposure, with a 15-year lag, was a strong predictor of lung cancer (p = 0.0001), with consistency across studies (test for heterogeneity, p = 0.34). Results for the log of cumulative exposure were consistent between underground mines and other facilities. Categorical analyses by quintile of cumulative exposure resulted in a monotonic trend with odds ratios of 1.0. 1.0, 1.3, 1.5, 1.6. Analyses using a spline curve also showed a monotonic increase in risk with increasing exposure. The estimated excess lifetime risk (through age 75) of lung cancer for a worker exposed from age 20 to 65 at 0.1 mg/m3 respirable crystalline silica (the permissible level in many countries) was 1.1-1.7%, above background risks of 3-6%. CONCLUSIONS: Our results support the decision by the IARC to classify inhaled silica in occupational settings as a carcinogen, and suggest that the current exposure limits in many countries may be inadequate. These data represent the first quantitative exposure-response analysis and risk assessment for silica using data from multiple studies.

A biomathematical model of particle clearance and retention in the lungs of coal miners.

To understand better the factors influencing the relationships among airborne particle exposure, lung burden, and fibrotic lung disease, we developed a biologically based kinetic model to predict the long-term retention of particles in the lungs of coal miners. This model includes alveolar, interstitial, and hilar lymph node compartments. The 131 miners in this study had worked in the Beckley, West Virginia, area and died during the 1960s. The data used to develop this model include exposure to respirable coal mine dust by intensity and duration within each job, lung and lymph node dust burdens at autopsy, pathological classification of fibrotic lung disease, and smoking history. Initial parameter estimates for this model were based on both human and animal data of particle deposition and clearance and on the biological and physical factors influencing these processes. Parameter estimation and model fit to the data were determined using least squares. Results show that the end-of-life lung dust burdens in these coal miners were substantially higher than expected from first-order clearance kinetics, yet lower than expected from the overloading of alveolar clearance predicted from rodent studies. The best-fitting and most parsimonious model includes processes for first-order alveolar-macrophage-mediated clearance and transfer of particles to the lung interstitium. These results are consistent with the particle retention patterns observed previously in the lungs of primates. The findings indicate that rodent models extrapolated to humans, without adjustment for the kinetic differences in particle clearance and retention, would be inadequate for predicting lung dust burdens in humans. Also, this human lung kinetic model predicts greater retained lung dust burdens from occupational exposure than predicted from current human models based on lower exposure data. This model is useful for risk assessment of particle-induced lung diseases, by estimating equivalent internal doses in rodents and humans and predicting lung burdens in humans with occupational dust exposures.

Methodological issues of using observational human data in lung dosimetry models for particulates.

INTRODUCTION: The use of human data to calibrate and validate a physiologically based pharmacokinetic (PBPK) model has the clear advantage of pertaining to the species of interest, namely humans. A challenge in using these data is their often sparse, heterogeneous nature, which may require special methods. Approaches for evaluating sources of variability and uncertainty in a human lung dosimetry model are described in this study. METHODS: A multivariate optimization procedure was used to fit a dosimetry model to data of 131 U.S. coal miners. These data include workplace exposures and end-of-life particle burdens in the lungs and hilar lymph nodes. Uncertainty in model structure was investigated by fitting various model forms for particle clearance and sequestration of particles in the lung interstitium. A sensitivity analysis was performed to determine which model parameters had the most influence on model output. Distributions of clearance parameters were estimated by fitting the model to each individual's data, and this information was used to predict inter-individual differences in lung particle burdens at given exposures. The influence of smoking history, race and pulmonary fibrosis on the individual's estimated clearance parameters was also evaluated. RESULTS: The model structure that provided the best fit to these coal miner data includes a first-order interstitialization process and no dose-dependent decline in alveolar clearance. The parameter that had the largest influence on model output is fractional deposition. Race and fibrosis severity category were statistically significant predictors of individual's estimated alveolar clearance rate coefficients (P < 0.03 and P < 0.01-0.06, respectively), but smoking history (ever, never) was not (P < 0.4). Adjustments for these group differences provided some improvement in the dosimetry model fit (up to 25% reduction in the mean squared error), although unexplained inter-individual differences made up the largest source of variability. Lung burdens were inversely associated with the miners' estimated clearance parameters, e.g. individuals with slower estimated clearance had higher observed lung burdens. CONCLUSIONS: The methods described in this study were used to examine issues of uncertainty in the model structure and variability of the miners' estimated clearance parameters. Estimated individual clearance had a large influence on predicted lung burden, which would also affect disease risk. These findings are useful for risk assessment, by providing estimates of the distribution of lung burdens expected under given exposure conditions.

Identifying high-risk small business industries for occupational safety and health interventions.

BACKGROUND: Approximately one-third (32%) of U.S. workers are employed in small business industries (those with 80% of workers in establishments with fewer than 100 employees), and approximately 53 million persons in private industry work in small business establishments. This study was performed to identify small business industries at high risk for occupational injuries, illnesses, and fatalities. METHODS: Small business industries were identified from among all three- and four-digit Standard Industrial Classification (SIC) codes and ranked using Bureau of Labor Statistics (BLS) data by rates and numbers of occupational injuries, illnesses, and fatalities. Both incidence rates and number of injury, illness, and fatality cases were evaluated. RESULTS: The 253 small business industries identified accounted for 1,568 work-related fatalities (34% of all private industry). Transportation incidents and violent acts were the leading causes of these fatalities. Detailed injury and illness data were available for 105 small business industries, that accounted for 1,476,400 work-related injuries, and 55,850 occupational illnesses. Many of the small business industries had morbidity and mortality rates exceeding the average rates for all private industry. The highest risk small business industries, based on a combined morbidity and mortality index, included logging, cut stone and stone products, truck terminals, and roofing, siding, and sheet metal work. CONCLUSIONS: Identification of high-risk small business industries indicates priorities for those interested in developing targeted prevention programs.

Crystalline silica exposure and lung cancer mortality in diatomaceous earth industry workers: a quantitative risk assessment.

OBJECTIVE: To use various exposure-response models to estimate the risk of mortality from lung cancer due to occupational exposure to respirable crystalline silica dust. METHODS: Data from a cohort mortality study of 2342 white male California diatomaceous earth mining and processing workers exposed to crystalline silica dust (mainly cristobalite) were reanalyzed with Poisson regression and Cox's proportional hazards models. Internal and external adjustments were used to control for potential confounding from the effects of time since first observation, calendar time, age, and Hispanic ethnicity. Cubic smoothing spline models were used to assess the fit of the models. Exposures were lagged by 10 years. Evaluations of the fit of the models were performed by comparing their deviances. Lifetime risks of lung cancer were estimated up to age 85 with an actuarial approach that accounted for competing causes of death. RESULTS: Exposure to respirable crystalline silica dust was a significant predictor (p<0.05) in nearly all of the models evaluated and the linear relative rate model with a 10 year exposure lag seemed to give the best fit in the Poisson regression analysis. For those who died of lung cancer the linear relative rate model predicted rate ratios for mortality from lung cancer of about 1.6 for the mean cumulative exposure to respirable silica compared with no exposure. The excess lifetime risk (to age 85) of mortality from lung cancer for white men exposed for 45 years and with a 10 year lag period at the current Occupational Safety and Health Administration (OSHA) standard of about 0.05 mg/m(3) for respirable cristobalite dust is 19/1000 (95% confidence interval (95% CI) 5/1000 to 46/1000). CONCLUSIONS: There was a significant risk of mortality from lung cancer that increased with cumulative exposure to respirable crystalline silica dust. The predicted number of deaths from lung cancer suggests that current occupational health standards may not be adequately protecting workers from the risk of lung cancer.

Human cancer risk and exposure to 1,3-butadiene--a tale of mice and men.

OBJECTIVES: The purpose of this study was to evaluate empirically the relevance of animal-bioassay-based models for predicting human risks from exposure to 1,3-butadiene (BD) using epidemiologic data. METHODS: Relative-risk results obtained with a regression model in a recent epidemiologic study were used to estimate leukemia risk for occupational and environmental exposures to BD and to compare these estimates with those previously derived from an analysis of animal bioassay data. RESULTS: The estimates of risk were found to be highly dependent on the model used when low levels of exposure were evaluated that are of environmental concern, but not at the levels of occupational concern. For example, at the level (1 part per million) of the recently revised standard of the Occupational Safety and Health Administration in the United States the estimates of lifetime excess risk ranged from 1 to 8 per 1000 workers. The range of the risk estimates derived from the epidemiologic models was remarkably similar to the range of risk estimates for occupational exposures (1 to 9 per thousand) previously developed by Dankovic et al in 1993 from an analysis of a mouse bioassay study for lymphocytic lymphoma. CONCLUSIONS: Results for BD seem to provide another example of a high degree of concordance between the risk predictions from models of toxicologic and epidemiologic data, particularly at occupational levels of exposure.