Use of the "Exposome" in the Practice of Epidemiology: A Primer on -Omic Technologies.

The exposome has been defined as the totality of exposures individuals experience over the course of their lives and how those exposures affect health. Three domains of the exposome have been identified: internal, specific external, and general external. Internal factors are those that are unique to the individual, and specific external factors include occupational exposures and lifestyle factors. The general external domain includes sociodemographic factors such as educational level and financial status. Eliciting information on the exposome is daunting and not feasible at present; the undertaking may never be fully realized. A variety of tools have been identified to measure the exposome. Biomarker measurements will be one of the major tools in exposomic studies. However, exposure data can also be obtained from other sources such as sensors, geographic information systems, and conventional tools such as survey instruments. Proof-of-concept studies are being conducted that show the promise of exposomic investigation and the integration of different kinds of data. The inherent value of exposomic data in epidemiologic studies is that they can provide greater understanding of the relationships among a broad range of chemical and other risk factors and health conditions and ultimately lead to more effective and efficient disease prevention and control.

Detection and measurement of surface contamination by multiple antineoplastic drugs using multiplex bead assay.

OBJECTIVES: Contamination of workplace surfaces by antineoplastic drugs presents an exposure risk for healthcare workers. Traditional instrumental methods to detect contamination such as liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) are sensitive and accurate but expensive. Since immunochemical methods may be cheaper and faster than instrumental methods, we wanted to explore their use for routine drug residue detection for preventing worker exposure. METHODS: In this study we examined the feasibility of using fluorescence covalent microbead immunosorbent assay (FCMIA) for simultaneous detection and semi-quantitative measurement of three antineoplastic drugs (5-fluorouracil, paclitaxel, and doxorubicin). The concentration ranges for the assay were 0-1000 ng/ml for 5-fluorouracil, 0-100 ng/ml for paclitaxel, and 0-2 ng/ml for doxorubicin. The surface sampling technique involved wiping a loaded surface with a swab wetted with wash buffer, extracting the swab in storage/blocking buffer, and measuring drugs in the extract using FCMIA. RESULTS: There was no significant cross-reactivity between these drugs at the ranges studied indicated by a lack of response in the assay to cross analytes. The limit of detection (LOD) for 5-fluorouracil on the surface studied was 0.93 ng/cm(2) with a limit of quantitation (LOQ) of 2.8 ng/cm(2), the LOD for paclitaxel was 0.57 ng/cm(2) with an LOQ of 2.06 ng/cm(2), and the LOD for doxorubicin was 0.0036 ng/cm(2) with an LOQ of 0.013 ng/cm(2). CONCLUSION: The use of FCMIA with a simple sampling technique has potential for low cost simultaneous detection and semi-quantitative measurement of surface contamination from multiple antineoplastic drugs.

Detection of 5-fluorouracil surface contamination in near real time.

OBJECTIVES: Contamination of workplace surfaces by antineoplastic drugs presents an exposure risk for healthcare workers. Traditional instrumental methods to detect contamination such as gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) are sensitive and accurate but expensive and incapable of producing results in real time. This limits their utility in preventing worker exposure. We are currently developing monitors based on lateral flow immunoassay that can detect drug contamination in near real time. In this report, we describe the laboratory performance of a 5-fluorouracil (5-FU) monitor. METHODS: The monitor was evaluated by spiking ceramic, vinyl, composite, stainless steel, and glass surfaces of 100 cm(2) area with 5-FU masses of 0, 5, 10, 25, 50, and 100 ng. The surface was sampled with a wetted cotton swab, the swab was extracted with buffer, and the resulting solution was applied to a lateral flow monitor. Two ways of evaluating the response of these monitors were used: an electronic method where a lateral flow reader was used for measuring line intensities, and a visual method where the intensity of the test line was visually compared to the control line. RESULTS: The 5-FU monitor is capable of detecting 10 ng/100 cm(2) (0.1 ng/cm(2)) using the electronic reader and 25 ng/100 cm(2) (0.25 ng/cm(2)) using the visual comparison method for the surfaces studied. The response of the monitors was compared to LC-MS/MS results for the same samples for validation and there was good correlation of the two methods but some differences in absolute response, especially at higher spiking levels for the surface samples.

Systems Biology and Biomarkers of Early Effects for Occupational Exposure Limit Setting.

In a recent National Research Council document, new strategies for risk assessment were described to enable more accurate and quicker assessments. This report suggested that evaluating individual responses through increased use of bio-monitoring could improve dose-response estimations. Identification of specific biomarkers may be useful for diagnostics or risk prediction as they have the potential to improve exposure assessments. This paper discusses systems biology, biomarkers of effect, and computational toxicology approaches and their relevance to the occupational exposure limit setting process. The systems biology approach evaluates the integration of biological processes and how disruption of these processes by chemicals or other hazards affects disease outcomes. This type of approach could provide information used in delineating the mode of action of the response or toxicity, and may be useful to define the low adverse and no adverse effect levels. Biomarkers of effect are changes measured in biological systems and are considered to be preclinical in nature. Advances in computational methods and experimental -omics methods that allow the simultaneous measurement of families of macromolecules such as DNA, RNA, and proteins in a single analysis have made these systems approaches feasible for broad application. The utility of the information for risk assessments from -omics approaches has shown promise and can provide information on mode of action and dose-response relationships. As these techniques evolve, estimation of internal dose and response biomarkers will be a critical test of these new technologies for application in risk assessment strategies. While proof of concept studies have been conducted that provide evidence of their value, challenges with standardization and harmonization still need to be overcome before these methods are used routinely.

Turning Numbers into Knowledge: Sensors for Safety, Health, Well-being, and Productivity.

The industrial hygiene community has witnessed exponential growth in the use of sensors, especially by individuals. Remote wireless sensors are now monitoring worker health, the environment, agriculture, work sites, disaster relief, and "smart" buildings and facilities.

Recommendations for biomonitoring of emergency responders: focus on occupational health investigations and occupational health research.

The disaster environment frequently presents rapidly evolving and unpredictable hazardous exposures to emergency responders. Improved estimates of exposure and effect from biomonitoring can be used to assess exposure-response relationships, potential health consequences, and effectiveness of control measures. Disaster settings, however, pose significant challenges for biomonitoring. A decision process for determining when to conduct biomonitoring during and following disasters was developed. Separate but overlapping decision processes were developed for biomonitoring performed as part of occupational health investigations that directly benefit emergency responders in the short term and for biomonitoring intended to support research studies. Two categories of factors critical to the decision process for biomonitoring were identified: Is biomonitoring appropriate for the intended purpose and is biomonitoring feasible under the circumstances of the emergency response? Factors within these categories include information needs, relevance, interpretability, ethics, methodology, and logistics. Biomonitoring of emergency responders can be a valuable tool for exposure and risk assessment. Information needs, relevance, and interpretability will largely determine if biomonitoring is appropriate; logistical factors will largely determine if biomonitoring is feasible. The decision process should be formalized and may benefit from advance planning.

Sampling and mass spectrometric analytical methods for five antineoplastic drugs in the healthcare environment.

CONTEXT: Healthcare worker exposure to antineoplastic drugs continues to be reported despite safe handling guidelines published by several groups. Sensitive sampling and analytical methods are needed so that occupational safety and health professionals may accurately assess environmental and biological exposure to these drugs in the workplace. OBJECTIVE: To develop liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analytical methods for measuring five antineoplastic drugs in samples from the work environment, and to apply these methods in validating sampling methodology. A single method for quantifying several widely used agents would decrease the number of samples required for method development, lower cost, and time of analysis. METHODS: for measuring these drugs in workers' urine would also be useful in monitoring personal exposure levels. RESULTS: LC-MS/MS methods were developed for individual analysis of five antineoplastic drugs in wipe and air sample media projected for use in field sampling: cyclophosphamide, ifosfamide, paclitaxel, doxorubicin, and 5-fluorouracil. Cyclophosphamide, ifosfamide, and paclitaxel were also measured simultaneously in some stages of the work. Extraction methods for air and wipe samples were developed and tested using the aforementioned analytical methods. Good recoveries from the candidate air and wipe sample media for most of the compounds, and variable recoveries for test wipe samples depending on the surface under study, were observed. Alternate LC-MS/MS methods were also developed to detect cyclophosphamide and paclitaxel in urine samples. CONCLUSIONS: The sampling and analytical methods were suitable for determining worker exposure to antineoplastics via surface and breathing zone contamination in projected surveys of healthcare settings.

Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers.

OBJECTIVE: This study evaluated health care worker exposure to antineoplastic drugs. METHODS: A cross-sectional study examined environmental samples from pharmacy and nursing areas. A 6-week diary documented tasks involving those drugs. Urine was analyzed for two specific drugs, and blood samples were analyzed by the comet assay. RESULTS: Sixty-eight exposed and 53 nonexposed workers were studied. Exposed workers recorded 10,000 drug-handling events during the 6-week period. Sixty percent of wipe samples were positive for at least one of the five drugs measured. Cyclophosphamide was most commonly detected, followed by 5-fluorouracil. Three of the 68 urine samples were positive for one drug. No genetic damage was detected in exposed workers using the comet assay. CONCLUSIONS: Despite following recommended safe-handling practices, workplace contamination with antineoplastic drugs in pharmacy and nursing areas continues at these locations.

DNA damage in leukocytes of workers occupationally exposed to 1-bromopropane.

1-bromopropane (1-BP; n-propyl bromide) (CAS No. 106-94-5) is an alternative to ozone-depleting chlorofluorocarbons that has a variety of potential applications as a degreasing agent for metals and electronics, and as a solvent vehicle for spray adhesives. Its isomer, 2-brompropane (2-BP; isopropyl bromide) (CAS No. 75-26-3) impairs antioxidant cellular defenses, enhances lipid peroxidation, and causes DNA damage in vitro. The present study had two aims. The first was to assess DNA damage in human leukocytes exposed in vitro to 1- or 2-BP. DNA damage was also assessed in peripheral leukocytes from workers with occupational exposure to 1-BP. In the latter assessment, start-of- and end-of-work week blood and urine samples were collected from 41 and 22 workers at two facilities where 1-BP was used as a solvent for spray adhesives in foam cushion fabrication. Exposure to 1-BP was assessed from personal-breathing zone samples collected for 1-3 days up to 8h per day for calculation of 8h time weighted average (TWA) 1-BP concentrations. Bromide (Br) was measured in blood and urine as a biomarker of exposure. Overall, 1-BP TWA concentrations ranged from 0.2 to 271 parts per million (ppm) at facility A, and from 4 to 27 ppm at facility B. The highest exposures were to workers classified as sprayers. 1-BP TWA concentrations were statistically significantly correlated with blood and urine Br concentrations. The comet assay was used to estimate DNA damage. In vitro, 1- or 2-BP induced a statistically significant increase in DNA damage at 1mM. In 1-BP exposed workers, start-of- and end-of-workweek comet endpoints were stratified based on job classification. There were no significant differences in DNA damage in leukocytes between workers classified as sprayers (high 1-BP exposure) and those classified as non-sprayers (low 1-BP exposure). At the facility with the high exposures, comparison of end-of-week values with start-of-week values using paired analysis revealed non-sprayers had significantly increased comet tail moments, and sprayers had significantly increased comet tail moment dispersion coefficients. A multivariate analysis included combining the data sets from both facilities, log transformation of 1-BP exposure indices, and the use of multiple linear regression models for each combination of DNA damage and exposure indices including exposure quartiles. The covariates were gender, age, smoking status, facility, and glutathione S-transferase M1 and T1 (GSTM1, GSTT1) polymorphisms. In the regression models, start-of-week comet tail moment in leukocytes was significantly associated with serum Br quartiles. End-of-week comet tail moment was significantly associated with 1-BP TWA quartiles, and serum Br quartiles. Gender, facility, and GSTM1 had a significant effect in one or more models. Additional associations were not identified from assessment of dispersion coefficients. In vitro and in vivo results provide limited evidence that 1-BP exposure may pose a small risk for increasing DNA damage.