Transcription factors WT1 and p53 combined: a prognostic biomarker in ovarian cancer.

BACKGROUND: New approaches to ovarian cancer are needed to improve survival. Wilms' tumour 1 (WT1) is a tumour-associated antigen expressed in many ovarian cancers. P53 is also often altered. The clinical significance of the combined expression of these two transcription factors has not been studied. METHODS: One hundred ninety-six ovarian tumours were classified histopathologically. Tumours were stained for WT1 and p53 immunohistochemically. Stains were analysed according to tumour type, grade and FIGO stage. Kaplan-Meier analyses on 96 invasive carcinomas determined whether categorical variables were related to survival. RESULTS: WT1 and p53 were related to ovarian tumour type, grade, FIGO stage and patient survival. Uniform nuclear p53 expression was associated with invasion and WT1 expression was associated with advanced grade, FIGO stage and poor survival. When WT1 and p53 were both in the age-adjusted Cox model, WT1 was significant while p53 was not. When we combined tumours expressing WT1 and p53, then adjusted for age and tumour subtype, the hazard ratio compared to tumours without WT1 and with normal p53 was 2.70; when adjusted for age and FIGO stage, the hazard ratio was 2.40. CONCLUSIONS: WT1, an antigen target, is a biomarker for poor prognosis, particularly when combined with altered p53.

Is beryllium-induced lung cancer caused only by soluble forms and high exposure levels?

OBJECTIVES: The US Occupational Safety and Health Administration (OSHA) recently proposed a permissible exposure limit of 0.2 µg/m3 for beryllium, based partly on extrapolated estimates of lung cancer risk from a pooled occupational cohort. The purpose of the present analysis was to evaluate whether cohort members exposed at lower levels to mainly insoluble forms of beryllium exhibit increased risk of lung cancer. METHODS: We conducted Cox proportional hazards regression analyses among 75 lung cancer cases in age-based risk sets within two lower exposure plants in the pooled cohort followed from 1940 to 2005. We used categorical and power models to evaluate exposure-response patterns for mean and cumulative beryllium exposures in the two-plant cohort, comparing findings with the full pooled cohort. We also evaluated the distribution of exposure-years in each cohort by solubility class (soluble, insoluble and mixed). RESULTS: 98% of workers in the two-plant cohort were hired between 1955 and 1969. The mean beryllium exposure averaged 1.3 µg/m3 and the predominant form was insoluble. Adjusting for confounders, we observed a monotonic increase in lung cancer mortality across exposure categories in the two-plant cohort. The exposure-response coefficients (per unit ln exposure) were 0.270 (p=0.061) for mean exposure and 0.170 (p=0.033) for cumulative exposure, compared with 0.155 and 0.094 (respectively) in the full cohort. CONCLUSION: The low-exposure levels at these two plants and the predominance of insoluble beryllium suggest that the overall pooled cohort findings on which OSHA's lung cancer risk assessment is based are relevant for current workers exposed to any form of beryllium.

Air, hand wipe, and surface wipe sampling for Bisphenol A (BPA) among workers in industries that manufacture and use BPA in the United States.

For decades, bisphenol A (BPA) has been used in making polycarbonate, epoxy, and phenolic resins and certain investment casting waxes, yet published exposure data are lacking for U.S. manufacturing workers. In 2013-2014, BPA air and hand exposures were quantified for 78 workers at six U.S. companies making BPA or BPA-based products. Exposure measures included an inhalable-fraction personal air sample on each of two consecutive work days (n = 146), pre- and end-shift hand wipe samples on the second day (n = 74 each), and surface wipe samples (n = 88). Potential determinants of BPA air and end-shift hand exposures (after natural log transformation) were assessed in univariate and multiple regression mixed models. The geometric mean (GM) BPA air concentration was 4.0 µg/m3 (maximum 920 µg/m3). The end-shift GM BPA hand level (26 µg/sample) was 10-times higher than the pre-shift level (2.6 µg/sample). BPA air and hand exposures differed significantly by industry and job. BPA air concentrations and end-shift hand levels were highest in the BPA-filled wax manufacturing/reclaim industry (GMAir = 48 µg/m3, GMHand-End = 130 µg/sample) and in the job of working with molten BPA-filled wax (GMAir = 43 µg/m3, GMHand-End = 180 µg/sample), and lowest in the phenolic resins industry (GMAir = 0.85 µg/m3, GMHand-End = 0.43 µg/sample) and in the job of flaking phenolic resins (GMAIR = 0.62 µg/m3, GMHand-End = 0.38 µg/sample). Determinants of increased BPA air concentration were industry, handling BPA containers, spilling BPA, and spending ≥50% of the shift in production areas; increasing age was associated with lower air concentrations. BPA hand exposure determinants were influenced by high values for two workers; for all other workers, tasks involving contact with BPA-containing materials and spending ≥50% of the shift in production areas were associated with increased BPA hand levels. Surface wipe BPA levels were significantly lower in eating/office areas (GM = 9.3 µg/100 cm2) than in production areas (GM = 140 µg/100 cm2). In conclusion, worker BPA exposure was associated with tasks and conditions affecting both inhalation and dermal exposure. The potential for BPA-related health effects among these workers is unknown.

Phosphorylation of eIF4E serine 209 is associated with tumour progression and reduced survival in malignant melanoma.

BACKGROUND: Melanoma is a disease that primarily arises in the skin but is a derivative of the neural crest. Eukaryotic translation initiation factor 4E (eIF4E) regulates translation of multiple malignancy-associated mRNAs and is overexpressed in many epithelial tumours. However, expression in human tumours derived from the neural crest is unknown. Here, we determined the association of eIF4E and phospho-eIF4E expression in melanocytic lesions with malignant conversion, metastatic potential and patient survival. METHODS: Archived formalin-fixed, paraffin-embedded surgical specimens from 114 patients with melanocytic lesions were stained immunohistochemically for eIF4E and phospho-eIF4E and evaluated semiquantitatively. The relationship between cytoplasmic and nuclear eIF4E and phospho-eIF4E protein expression, melanocytic lesion subtype and tumour progression was determined. Kaplan-Meier survival analyses and Cox proportional hazard regression were performed. RESULTS: Increased eIF4E and phospho-eIF4E expression was highly associated with malignancy (P<0.0001). High nuclear phospho-eIF4E was associated with synchronous or future metastasis (P=0.0059). Kaplan-Meier analyses demonstrated highly significant associations between high histoscores for cytoplasmic and nuclear phospho-eIF4E and reduced survival in all patients (P=0.0003 and 0.0009, respectively). CONCLUSIONS: Increased melanoma expression of eIF4E and phospho-eIF4E is associated with metastatic potential, reduced survival and increased risk of death.

Birth defects in infants born to employees of a microelectronics and business machine manufacturing facility.

BACKGROUND: Concerns about solvent releases from a microelectronics/business machine manufacturing facility in upstate New York led to interest in the health of former workers, including this investigation of birth defects in children of male and female employees. METHODS: Children born 1983 to 2001 to facility employees were enumerated and matched to New York State's Congenital Malformations Registry. Reported structural birth defects were compared with numbers expected from state rates (excluding New York City), generating standardized prevalence ratios (SPRs). Exposure assessors classified employees as ever/never potentially exposed at the facility to metals, chlorinated hydrocarbons, and other hydrocarbons during windows critical to organogenesis (female workers) or spermatogenesis (male workers). Among workers, adjusted prevalence ratios were generated to evaluate associations between potential exposures and specific birth defects. RESULTS: External comparisons for structural defects were at expectation for infants of male workers (SPR = 1.01; 95% confidence interval [CI], 0.77-1.29; n = 60) and lower for births to female workers (SPR = 0.84; 95% CI, 0.50-1.33; n = 18). Among full-term infants of male workers, ventricular septal defects (VSDs) were somewhat elevated compared with the general population (SPR = 1.58; 95% CI, 0.99-2.39; n = 22). Within the cohort, potential paternal metal exposure was associated with increased VSD risk (adjusted prevalence ratio = 2.70; 95% CI, = 1.09-6.67; n = 7). CONCLUSION: While overall SPRs were near expectation, paternal exposure to metals (primarily lead) appeared to be associated with increased VSD risk in infants. Take-home of occupational exposures, nonoccupational exposures, and chance could not be ruled out as causes. Case numbers for many defects were small, limiting assessment of the role of occupational exposures. Birth Defects Research (Part A) 106:696-707, 2016. © 2016 Wiley Periodicals, Inc.

Carbon Nanotube and Nanofiber Exposure Assessments: An Analysis of 14 Site Visits.

Recent evidence has suggested the potential for wide-ranging health effects that could result from exposure to carbon nanotubes (CNT) and carbon nanofibers (CNF). In response, the National Institute for Occupational Safety and Health (NIOSH) set a recommended exposure limit (REL) for CNT and CNF: 1 µg m(-3) as an 8-h time weighted average (TWA) of elemental carbon (EC) for the respirable size fraction. The purpose of this study was to conduct an industrywide exposure assessment among US CNT and CNF manufacturers and users. Fourteen total sites were visited to assess exposures to CNT (13 sites) and CNF (1 site). Personal breathing zone (PBZ) and area samples were collected for both the inhalable and respirable mass concentration of EC, using NIOSH Method 5040. Inhalable PBZ samples were collected at nine sites while at the remaining five sites both respirable and inhalable PBZ samples were collected side-by-side. Transmission electron microscopy (TEM) PBZ and area samples were also collected at the inhalable size fraction and analyzed to quantify and size CNT and CNF agglomerate and fibrous exposures. Respirable EC PBZ concentrations ranged from 0.02 to 2.94 µg m(-3) with a geometric mean (GM) of 0.34 µg m(-3) and an 8-h TWA of 0.16 µg m(-3). PBZ samples at the inhalable size fraction for EC ranged from 0.01 to 79.57 µg m(-3) with a GM of 1.21 µg m(-3). PBZ samples analyzed by TEM showed concentrations ranging from 0.0001 to 1.613 CNT or CNF-structures per cm(3) with a GM of 0.008 and an 8-h TWA concentration of 0.003. The most common CNT structure sizes were found to be larger agglomerates in the 2-5 µm range as well as agglomerates >5 µm. A statistically significant correlation was observed between the inhalable samples for the mass of EC and structure counts by TEM (Spearman ρ = 0.39, P < 0.0001). Overall, EC PBZ and area TWA samples were below the NIOSH REL (96% were <1 µg m(-3) at the respirable size fraction), while 30% of the inhalable PBZ EC samples were found to be >1 µg m(-3). Until more information is known about health effects associated with larger agglomerates, it seems prudent to assess worker exposure to airborne CNT and CNF materials by monitoring EC at both the respirable and inhalable size fractions. Concurrent TEM samples should be collected to confirm the presence of CNT and CNF.

Trends in worker hearing loss by industry sector, 1981-2010.

BACKGROUND: The purpose of this study was to estimate the incidence and prevalence of hearing loss for noise-exposed U.S. workers by industry sector and 5-year time period, covering 30 years. METHODS: Audiograms for 1.8 million workers from 1981-2010 were examined. Incidence and prevalence were estimated by industry sector and time period. The adjusted risk of incident hearing loss within each time period and industry sector as compared with a reference time period was also estimated. RESULTS: The adjusted risk for incident hearing loss decreased over time when all industry sectors were combined. However, the risk remained high for workers in Healthcare and Social Assistance, and the prevalence was consistently high for Mining and Construction workers. CONCLUSIONS: While progress has been made in reducing the risk of incident hearing loss within most industry sectors, additional efforts are needed within Mining, Construction and Healthcare and Social Assistance.

Mortality among a cohort of U.S. commercial airline cockpit crew.

BACKGROUND: We evaluated mortality among 5,964 former U.S. commercial cockpit crew (pilots and flight engineers). The outcomes of a priori interest were non-chronic lymphocytic leukemia, central nervous system (CNS) cancer (including brain), and malignant melanoma. METHODS: Vital status was ascertained through 2008. Life table and Cox regression analyses were conducted. Cumulative exposure to cosmic radiation was estimated from work history data. RESULTS: Compared to the U.S. general population, mortality from all causes, all cancer, and cardiovascular diseases was decreased, but mortality from aircraft accidents was highly elevated. Mortality was elevated for malignant melanoma but not for non-chronic lymphocytic leukemia. CNS cancer mortality increased with an increase in cumulative radiation dose. CONCLUSIONS: Cockpit crew had a low all-cause, all-cancer, and cardiovascular disease mortality but elevated aircraft accident mortality. Further studies are needed to clarify the risk of CNS and other radiation-associated cancers in relation to cosmic radiation and other workplace exposures.

Laparoscopic oviductal artificial insemination improves pregnancy success in exogenous gonadotropin-treated domestic cats as a model for endangered felids.

Artificial insemination (AI) in cats traditionally uses equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) to induce follicular development and ovulation, with subsequent bilateral laparoscopic intrauterine insemination. However, long-acting hCG generates undesirable secondary ovulations in cats. Uterine AI also requires relatively high numbers of spermatozoa for fertilization (~8 × 10(6) sperm), and unfortunately, sperm recovery from felids is frequently poor. Using short-acting porcine luteinizing hormone (pLH) instead of hCG, and using the oviduct as the site of sperm deposition, could improve fertilization success while requiring fewer spermatozoa. Our objectives were to compare pregnancy and fertilization success between 1) uterine and oviductal inseminations and 2) eCG/hCG and eCG/pLH regimens in domestic cats. Sixteen females received either eCG (100 IU)/hCG (75 IU) or eCG (100 IU)/pLH (1000 IU). All females ovulated and were inseminated in one uterine horn and the contralateral oviduct using fresh semen (1 × 10(6) motile sperm/site) from a different male for each site. Pregnant females (11/16; 69%) were spayed approximately 20 days post-AI, and fetal paternity was genetically determined. The number of corpora lutea (CL) at AI was similar between hormone regimens, but hCG increased the number of CL at 20 days post-AI. Numbers of pregnancies and normal fetuses were similar between regimens. Implantation abnormalities were observed in the hCG group only. Finally, oviductal AI produced more fetuses than uterine AI. In summary, laparoscopic oviductal AI with low sperm numbers in eCG/hCG- or eCG/pLH-treated females resulted in high pregnancy and fertilization percentages in domestic cats. Our subsequent successes with oviductal AI in eCG/pLH-treated nondomestic felids to produce healthy offspring supports cross-species applicability.

A prospective study of carpal tunnel syndrome: workplace and individual risk factors.

OBJECTIVES: To quantify the risk for carpal tunnel syndrome (CTS) from workplace physical factors, particularly hand activity level and forceful exertion, while taking into account individual factors including age, gender, body mass index (BMI), and pre-existing medical conditions. METHODS: Three healthcare and manufacturing workplaces were selected for inclusion on the basis of range of exposure to hand activity level and forceful exertion represented by their jobs. Each study participant's job tasks were observed and evaluated onsite and videotaped for further analysis, including frequency and duration of exertion and postural deviation. Individual health assessment entailed electrodiagnostic testing of median and ulnar nerves, physical examination and questionnaires at baseline with annual follow-up for 2 years. RESULTS: The incidence of dominant hand CTS during the study was 5.11 per 100 person-years (29 cases). Adjusted HRs for dominant hand CTS were as follows: working with forceful exertion ≥ 20% but <60% of the time: 2.83 (1.18, 6.79) and ≥ 60% of the time vs <20%: 19.57 (5.96, 64.24), BMI ≥ 30 kg/m(2) (obesity): 3.19 (1.28, 7.98). The American Conference for Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) for hand activity level also predicted CTS, HR=1.40 (1.11, 1.78) for each unit increase in the TLV ratio, controlling for obesity and job strain. CONCLUSIONS: Workplace and individual risk factors both contribute to the risk for CTS. Time spent in forceful exertion can be a greater risk for CTS than obesity if the job exposure is high. Preventive workplace efforts should target forceful exertions.

Carbon nanotube dosimetry: from workplace exposure assessment to inhalation toxicology.

BACKGROUND: Dosimetry for toxicology studies involving carbon nanotubes (CNT) is challenging because of a lack of detailed occupational exposure assessments. Therefore, exposure assessment findings, measuring the mass concentration of elemental carbon from personal breathing zone (PBZ) samples, from 8 U.S.-based multi-walled CNT (MWCNT) manufacturers and users were extrapolated to results of an inhalation study in mice. RESULTS: Upon analysis, an inhalable elemental carbon mass concentration arithmetic mean of 10.6 µg/m3 (geometric mean 4.21 µg/m3) was found among workers exposed to MWCNT. The concentration equates to a deposited dose of approximately 4.07 µg/d in a human, equivalent to 2 ng/d in the mouse. For MWCNT inhalation, mice were exposed for 19 d with daily depositions of 1970 ng (equivalent to 1000 d of a human exposure; cumulative 76 yr), 197 ng (100 d; 7.6 yr), and 19.7 ng (10 d; 0.76 yr) and harvested at 0, 3, 28, and 84 d post-exposure to assess pulmonary toxicity. The high dose showed cytotoxicity and inflammation that persisted through 84 d after exposure. The middle dose had no polymorphonuclear cell influx with transient cytotoxicity. The low dose was associated with a low grade inflammatory response measured by changes in mRNA expression. Increased inflammatory proteins were present in the lavage fluid at the high and middle dose through 28 d post-exposure. Pathology, including epithelial hyperplasia and peribronchiolar inflammation, was only noted at the high dose. CONCLUSION: These findings showed a limited pulmonary inflammatory potential of MWCNT at levels corresponding to the average inhalable elemental carbon concentrations observed in U.S.-based CNT facilities and estimates suggest considerable years of exposure are necessary for significant pathology to occur at that level.

Occupational exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers: mobile direct-reading sampling.

UNLABELLED: RESEARCH SIGNIFICANCE: Toxicological evidence suggests the potential for a wide range of health effects from exposure to carbon nanotubes (CNTs) and carbon nanofibers (CNFs). To date, there has been much focus on the use of direct-reading instruments (DRIs) to assess multiple airborne exposure metrics for potential exposures to CNTs and CNFs due to their ease of use and ability to provide instantaneous results. Still, uncertainty exists in the usefulness and interpretation of the data. To address this gap, air-monitoring was conducted at six sites identified as CNT and CNF manufacturers or users and results were compared with filter-based metrics. METHODS: Particle number, respirable mass, and active surface area concentrations were monitored with a condensation particle counter, a photometer, and a diffusion charger, respectively. The instruments were placed on a mobile cart and used as area monitors in parallel with filter-based elemental carbon (EC) and electron microscopy samples. Repeat samples were collected on consecutive days, when possible, during the same processes. All instruments in this study are portable and routinely used for industrial hygiene sampling. RESULTS: Differences were not observed among the various sampled processes compared with concurrent indoor or outdoor background samples while examining the different DRI exposure metrics. Such data were also inconsistent with results for filter-based samples collected concurrently at the same sites [Dahm MM, Evans DE, Schubauer-Berigan MK et al. (2012) Occupational exposure assessment in CNT and nanofiber primary and secondary manufacturers. Ann Occup Hyg; 56: 542-56]. Significant variability was seen between these processes as well as the indoor and outdoor backgrounds. However, no clear pattern emerged linking the DRI results to the EC or the microscopy data (CNT and CNF structure counts). CONCLUSIONS: Overall, no consistent trends were seen among similar processes at the various sites. The DRI instruments employed were limited in their usefulness in assessing and quantifying potential exposures at the sampled sites but were helpful for hypothesis generation, control technology evaluations, and other air quality issues. The DRIs employed are nonspecific, aerosol monitors, and, therefore, subject to interferences. As such, it is necessary to collect samples for analysis by more selective, time-integrated, laboratory-based methods to confirm and quantify exposures.

Prevalence of hearing loss in the United States by industry.

BACKGROUND: Twenty-two million workers are exposed to hazardous noise in the United States. The purpose of this study is to estimate the prevalence of hearing loss among U.S. industries. METHODS: We examined 2000-2008 audiograms for male and female workers ages 18-65, who had higher occupational noise exposures than the general population. Prevalence and adjusted prevalence ratios (PRs) for hearing loss were estimated and compared across industries. RESULTS: In our sample, 18% of workers had hearing loss. When compared with the Couriers and Messengers industry sub-sector, workers employed in Mining (PR = 1.65, CI = 1.57-1.73), Wood Product Manufacturing (PR = 1.65, CL = 1.61-1.70), Construction of Buildings (PR = 1.52, CI = 1.45-1.59), and Real Estate and Rental and Leasing (PR = 1.61, CL = 1.51-1.71) [corrected] had higher risks for hearing loss. CONCLUSIONS: Workers in the Mining, Manufacturing, and Construction industries need better engineering controls for noise and stronger hearing conservation strategies. More hearing loss research is also needed within traditional "low-risk" industries like Real Estate.

Use of and occupational exposure to indium in the United States.

Indium use has increased greatly in the past decade in parallel with the growth of flat-panel displays, touchscreens, optoelectronic devices, and photovoltaic cells. Much of this growth has been in the use of indium tin oxide (ITO). This increased use has resulted in more frequent and intense exposure of workers to indium. Starting with case reports and followed by epidemiological studies, exposure to ITO has been linked to serious and sometimes fatal lung disease in workers. Much of this research was conducted in facilities that process sintered ITO, including manufacture, grinding, and indium reclamation from waste material. Little has been known about indium exposure to workers in downstream applications. In 2009-2011, the National Institute for Occupational Safety and Health (NIOSH) contacted 89 potential indium-using companies; 65 (73%) responded, and 43 of the 65 responders used an indium material. Our objective was to identify current workplace applications of indium materials, tasks with potential indium exposure, and exposure controls being used. Air sampling for indium was either conducted by NIOSH or companies provided their data for a total of 63 air samples (41 personal, 22 area) across 10 companies. Indium exposure exceeded the NIOSH recommended exposure limit (REL) of 0.1 mg/m(3) for certain methods of resurfacing ITO sputter targets, cleaning sputter chamber interiors, and in manufacturing some inorganic indium compounds. Indium air concentrations were low in sputter target bonding with indium solder, backside thinning and polishing of fabricated indium phosphide-based semiconductor devices, metal alloy production, and in making indium-based solder pastes. Exposure controls such as containment, local exhaust ventilation (LEV), and tool-mounted LEV can be effective at reducing exposure. In conclusion, occupational hygienists should be aware that the manufacture and use of indium materials can result in indium air concentrations that exceed the NIOSH REL. Given recent findings of adverse health effects in workers, research is needed to determine if the current REL sufficiently protects workers against indium-related diseases.

Occupational exposure to diisononyl phthalate (DiNP) in polyvinyl chloride processing operations.

PURPOSE: Diisononyl phthalate (DiNP) is primarily used as a plasticizer in polyvinyl chloride (PVC) materials. While information is available on general population exposure to DiNP, occupational exposure data are lacking. We present DiNP metabolite urinary concentrations in PVC processing workers, estimate DiNP daily intake for these workers, and compare worker estimates to other populations. METHODS: We assessed DiNP exposure in participants from two companies that manufactured PVC materials, a PVC film manufacturer (n = 25) and a PVC custom compounder (n = 12). A mid-shift and end-shift urine sample was collected from each participant and analyzed for the DiNP metabolite mono(carboxy-isooctyl) phthalate (MCiOP). Mixed models were used to assess the effect on MCiOP concentrations of a worker being assigned to (1) a task using DiNP and (2) a shift where DiNP was used. A simple pharmacokinetic model was used to estimate DiNP daily intake from the MCiOP concentrations. RESULTS: Creatinine-adjusted MCiOP urinary concentrations ranged from 0.42-80 µg/g in PVC film and from 1.11-13.4 µg/g in PVC compounding. PVC film participants who worked on a task using DiNP (n = 7) had the highest MCiOP geometric mean (GM) end-shift concentration (25.2 µg/g), followed by participants who worked on a shift where DiNP was used (n = 11) (17.7 µg/g) as compared to participants with no task (2.92 µg/g) or shift (2.08 µg/g) exposure to DiNP. The GM end-shift MCiOP concentration in PVC compounding participants (4.80 µg/g) was comparable to PVC film participants with no task or shift exposure to DiNP. Because no PVC compounding participants were assigned to tasks using DINP on the day sampled, DiNP exposure in this company may be underestimated. The highest DiNP intake estimate was 26 µg/kg/day. CONCLUSION: Occupational exposure to DiNP associated with PVC film manufacturing tasks were substantially higher (sixfold to tenfold) than adult general population exposures; however, all daily intake estimates were less than 25% of current United States or European acceptable or tolerable daily intake estimates. Further characterization of DiNP occupational exposures in other industries is recommended.

Evaluating bias from birth-cohort effects in the age-based cox proportional hazards model.

The nested case-control design is frequently used to evaluate exposures and health outcomes within the confines of a cohort study. When incidence-density sampling is used to identify controls, the resulting data can be analyzed using conditional logistic regression (equivalent to stratified Cox proportional hazards regression). In these studies, exposure lagging is often used to account for disease latency. In light of recent criticism of incidence-density sampling, we used simulated occupational cohorts to evaluate age-based incidence-density sampling for lagged exposures in the presence of birth-cohort effects and associations among time-related variables. Effect estimates were unbiased when adjusted for birth cohort; however, unadjusted effect estimates were biased, particularly when age at hire and year of hire were correlated. When the analysis included an adjustment for birth cohort, the inclusion of lagged-out cases and controls (assigned a lagged exposure of zero) did not introduce bias.

Risk of lung cancer associated with quantitative beryllium exposure metrics within an occupational cohort.

OBJECTIVES: Beryllium has been identified as a human carcinogen on the basis of animal and epidemiological studies. The authors recently reported updated associations between lung cancer and beryllium exposure in a large, pooled occupational cohort. The authors conducted the present study to evaluate the shape of exposure-response associations between different exposure metrics and lung cancer in this cohort, considering potential confounders (race, plant, professional and short-term work status, and exposure to other lung carcinogens). METHODS: The authors conducted Cox proportional hazards regression analyses of lung cancer risk with cumulative, mean and maximum 'daily weighted average' (DWA) exposure among 5436 workers, using age-based risk sets. Different exposure-response curves were fitted to the exposure metrics, including categorical, power, restricted cubic spline and piecewise log-linear fits. RESULTS: The authors found significant positive associations between lung cancer and mean (p < 0.0001) and maximum (p < 0.0001) exposure, adjusting for age, birth cohort and plant, and for cumulative (p = 0.0017) beryllium exposure, adjusting for these factors plus short-term work status and exposure to asbestos. The best-fitting models were generally categorical or piecewise log-linear, with the steepest increase in lung cancer risk between 0 and 10 µg/m(3) for both mean and maximum DWA exposure and between 0 and 200 µg/m(3)-days for cumulative DWA exposure. The estimated mean DWA beryllium exposure associated with 10(-3) excess lifetime risk based on the piecewise log-linear model is 0.033 µg/m(3). CONCLUSION: This study provides evidence that lung cancer risk is elevated at levels near the current US Occupational Safety and Health Administration beryllium exposure limit of 2.0 µg/m(3) DWA for workers.

Cohort mortality study of workers at seven beryllium processing plants: update and associations with cumulative and maximum exposure.

OBJECTIVES: To extend follow-up of cause-specific mortality in workers at seven beryllium processing plants and to estimate associations between mortality risk and beryllium exposure. METHODS: 9199 workers were followed for mortality from 1940 through 2005. Standardised mortality ratios (SMRs) were estimated based on US population comparisons for lung, nervous system and urinary tract cancers, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and categories containing chronic beryllium disease (CBD) and cor pulmonale. Associations with maximum and cumulative exposure were calculated for a subset of the workers. RESULTS: Overall mortality in the cohort compared with the US population was elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR 1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR 7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to 1.26). Mortality rates for most diseases of interest increased with time-since-hire. For the category including CBD, rates were substantially elevated compared to the US population across all exposure groups. Workers whose maximum beryllium exposure was ≥ 10 µg/m(3) had higher rates of lung cancer, urinary tract cancer, COPD and the category containing cor pulmonale than workers with lower exposure. Significant positive trends with cumulative exposure were observed for nervous system cancers (p = 0.0006) and, when short-term workers were excluded, lung cancer (p = 0.01), urinary tract cancer (p = 0.003) and COPD (p < 0.0001). CONCLUSION: These findings reaffirm that lung cancer and CBD, and suggest that COPD and nervous system and urinary tract cancers, are related to beryllium exposure. Cigarette smoking and exposure to other lung carcinogens are unlikely to explain these elevations.

Maternal exposure to polychlorinated biphenyls and the secondary sex ratio: an occupational cohort study.

BACKGROUND: Though commercial production of polychlorinated biphenyls was banned in the United States in 1977, exposure continues due to their environmental persistence. Several studies have examined the association between environmental polychlorinated biphenyl exposure and modulations of the secondary sex ratio, with conflicting results. OBJECTIVE: Our objective was to evaluate the association between maternal preconceptional occupational polychlorinated biphenyl exposure and the secondary sex ratio. METHODS: We examined primipara singleton births of 2595 women, who worked in three capacitor plants at least one year during the period polychlorinated biphenyls were used. Cumulative estimated maternal occupational polychlorinated biphenyl exposure at the time of the infant's conception was calculated from plant-specific job-exposure matrices. A logistic regression analysis was used to evaluate the association between maternal polychlorinated biphenyl exposure and male sex at birth (yes/no). RESULTS: Maternal body mass index at age 20, smoking status, and race did not vary between those occupationally exposed and those unexposed before the child's conception. Polychlorinated biphenyl-exposed mothers were, however, more likely to have used oral contraceptives and to have been older at the birth of their first child than non-occupationally exposed women. Among 1506 infants liveborn to polychlorinated biphenyl-exposed primiparous women, 49.8% were male; compared to 49.9% among those not exposed (n = 1089). Multivariate analyses controlling for mother's age and year of birth found no significant association between the odds of a male birth and mother's cumulative estimated polychlorinated biphenyl exposure to time of conception. CONCLUSIONS: Based on these data, we find no evidence of altered sex ratio among children born to primiparous polychlorinated biphenyl-exposed female workers.

Analysis of lognormally distributed exposure data with repeated measures and values below the limit of detection using SAS.

Studies of determinants of occupational exposure frequently involve left-censored lognormally distributed data, often with repeated measures. Left censoring occurs when observations are below the analytical limit of detection (LOD); repeated measures data results from taking multiple measurements on the same worker. A common method of dealing with this type of data has been to substitute a value (such as LOD/2) for the censored data followed by statistical analysis using the 'usual' methods. Recently, maximum likelihood estimation (MLE) methods have been employed to reduce bias associated with the substitution method. We compared substitution and MLE methods using simulated lognormally distributed exposure data subjected to varying amounts of censoring using two procedures available in SAS: LIFEREG and NLMIXED. In these simulations, the MLE method resulted in less bias and performed well even for censoring up to 80%, whereas the substitution method resulted in considerable bias. We illustrate the NLMIXED procedure using a dataset of chlorpyrifos air measurements collected from termiticide applicators on consecutive days over a 5-day workweek. We provide sample SAS code for several situations including one and two groups, with and without repeated measures, random slopes, and nested random effects.