D. Gayle DeBord

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.

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.

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.(1) This report suggested that evaluating individual responses through increased use of bio-monitoring could improve dose-response estimations. Identi-fication 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.

4,4′-Methylenebis(2-chloroaniline) (MOCA): The Effect of Multiple Oral Administration, Route, and Phenobarbital Induction on Macromolecular Adduct Formation in the Rat

The effect of multiple oral administration of MOCA, a suspect human carcinogen, was studied in the adult male rat. As many as 28 consecutive daily doses of [14C]MOCA at 28.1 mumol/kg body wt (5 microCi/day) were administered and rats were euthanized at weekly intervals for 7 weeks. MOCA adduct formation for globin and serum albumin was evaluated by determination of [14C]MOCA covalent binding. The covalent binding associated with globin showed a linear increase over the 28-day exposure period with 342 fmol/mg globin 24 hr after the final dose. More extensive covalent binding was detected for albumin with 443 fmol/mg albumin after the final dose, but increases were not linear. After cessation of dosing, the albumin adduct levels decreased rapidly (t1/2 = 4.6 days) in relation to globin adduct levels (t1/2 = 16.1 days). The MOCA-globin adduct t1/2 is consistent with that determined after a single 281 mumol/kg oral dose of MOCA. Significant differences related to route of administration were detected for 24-hr globin covalent binding with ip greater than po greater than dermal. Distribution of undifferentiated [14C]MOCA was highest in the liver at 24 hr with tissue levels for liver greater than kidney greater than lung greater than spleen greater than testes greater than urinary bladder. Induction of cytochrome P450 enzymes by administration of phenobarbital (100 mg/kg/day/3 days) resulted in a significant (p less than 0.05) increase in MOCA-globin adduct formation detected with 33.5 pmol/mg globin for induced rats versus 13.6 pmol/mg globin for control rats. Although MOCA-globin and albumin adducts show differing stability, quantification of such MOCA adducts may be useful for long-term industrial biomonitoring of MOCA.

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.

ortho-Toluidine Blood Protein Adducts: HPLC Analysis with Fluorescence Detection after a Single Dose in the Adult Male Rat

Hemoglobin (Hb) and albumin (Alb) adducts of the suspect human carcinogen ortho-toluidine (OT) were quantified in blood samples collected from rats after a single i.p. injection. Mild alkaline hydrolysis of Hb adducted with [14C]OT followed by extraction with ethyl acetate resulted in recovery of 63% of the bound radioactivity. HPLC analysis revealed a single radiolabeled peak which was identified as OT by GC-MS. In subsequent experiments Hb and Alb adduct levels were determined by HPLC analysis of this cleavage product using fluorescence detection. 4-Ethylaniline was used as internal standard. The detection limit for OT was approximately 450 pg/injection or 5 pmol/mg Hb. Mean adduct levels for Hb increased rapidly over the first 4 hr with the highest (ng/mg Hb +/- SD) 3.7 +/- 0.5 detected 24 hr after OT administration at 50 mg/kg body wt. In contrast, adduct levels for pooled Alb samples increased from 0.7 ng/mg Alb at 2 hr to 2.5 ng/mg Alb at 4 hr, but were not detectable 24 hr after dosing. Hb adducts showed a linear relationship for OT doses of 10, 20, 40, 50, and 100 mg/kg body wt. The Hb adduct t1/2 (11 days) was determined after a single 100 mg/kg OT dose. Hb adduct levels were quantifiable (1.3 +/- 0.2 ng/mg Hb) by HPLC/fluorescence 28 days after 100 mg/kg OT. Although Hb and Alb adducts differ in stability, a ratio of such OT adducts may be useful in long-term industrial biomonitoring for evaluation of OT exposure.

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.

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/cm2 with a limit of quantitation (LOQ) of 2.8 ng/cm2, the LOD for paclitaxel was 0.57 ng/cm2 with an LOQ of 2.06 ng/cm2, and the LOD for doxorubicin was 0.0036 ng/cm2 with an LOQ of 0.013 ng/cm2. 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.

Clarification about hazardous drugs

We read with interest the article by Traynor[1][1] that appeared in the September 1 issue of AJHP and would like to clarify a potential misconception—that the National Institute for Occupational Safety and Health (NIOSH) recommends all hazardous drugs be handled in the same manner, regardless of

A Summary of the Workshop "Applying Biomarkers to Occupational Health Practice"

1National Institute for Occupational Safety and Health, Cincinnati, Ohio 2University of ErlangenNuremburg, Erlangen, Germany 3Occupational Safety and Health Administration, Washington, DC 4Johns Hopkins University, Baltimore, Md. 5Rohm and Haas, Co, Spring House, Pa. 6University of Maryland, Baltimore, Md. 7University of Washington, Seattle, Wash. 8Columbia University, New York, N.Y. 9University of Cincinnati, Cincinnati, Ohio 10Sapphire Group, Inc., Washington, DC 11University of Montreal, Montreal, Canada INTRODUCTION