Although prescription drugs for treating life-threatening illnesses like cancer or conditions that cause severe pain are highly beneficial to patients, they can be hazardous to workers who manufacture and test the drugs and the healthcare professionals who administer them. According to NIOSH, drugs should be considered hazardous if they exhibit one or more of the following characteristics in humans or animals: 
  • carcinogenicity
  • teratogenicity or other developmental toxicity
  • reproductive toxicity
  • organ toxicity at low doses
  • genotoxicity
In addition, NIOSH advises that new drugs should be considered hazardous if their structure and toxicity profiles mimic those of existing drugs determined to be hazardous by these criteria. Examples of hazardous drugs include those used for cancer, antiviral drugs, and hormones. 
International Society for Pharmaceutical Engineering: Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (2017).
NIOSH evaluates drugs based on these and other criteria and periodically updates its “List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings.” The list was most recently updated in September 2016. OSHA also provides guidance to identify, assess, and control occupational exposure to hazardous drugs and references the infrastructure program and management requirements outlined in the U.S. Pharmacopeial Convention (USP) chapter 797 and the pending chapter 800.  One might wonder why opioids such as fentanyl are not included on the NIOSH hazardous drugs list. Opioids, as a class of compounds, do not meet the criteria for designation as hazardous drugs because their health effects are acute when used in prescribed doses for brief periods of time. However, opioids do meet the criteria for highly potent drugs as defined by the International Society for Pharmaceutical Engineering’s Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products. ISPE uses the term “highly potent” to describe active pharmaceutical ingredients with a therapeutic dose at or below 10 milligrams. Generally, the pharmaceutical industry establishes internal occupational exposure limits at or below 10 µg/m3 as an eight-hour time-weighted average for highly potent drugs. For fentanyl, internal OELs are as low as 0.1 µg/m3 to protect workers from adverse effects that can be associated with occupational exposure. Historically, assessment of workplace exposure to hazardous and highly potent drugs has been a unique concern of industrial hygienists practicing in pharmaceutical manufacturing. These environments are strictly controlled and regulated to protect product, people, and facilities. Redundant engineering controls and containment, in addition to personal protective equipment, are common. In 2004, the NIOSH publication “Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings,” commonly known as the hazardous drug alert, helped increase awareness of workplace exposure risk to hazardous drugs in less controlled downstream environments, including pharmacy compounding and clinical administration. The pending USP 800 standard, which addresses sampling for residual hazardous drugs, has been developed in response to these concerns. More recently, illicit manufacture and use of opioids has led to concerns that workers in uncontrolled environments (including first responders and remediation workers) as well as the general public are at risk for potential exposures. What can we learn from the pharmaceutical industry about assessing exposure risks to hazardous drugs, including illicit drugs, in these uncontrolled environments? EXPOSURE STANDARDS AND LIMITS Most hazardous drugs are solids at room temperature, with very low or insignificant vapor pressure. Highly soluble hazardous drugs can be absorbed through the mucous membranes or even intact skin, so all routes of exposure must be considered; however, the primary route of industrial hygiene concern is aerosol inhalation. With few exceptions, regulatory or health-based OELs for drug materials are not readily available, but they do exist. Human clinical data is generated for drug candidates by the drug innovator during the approval process. As a result, the toxicology and pharmacology of drugs are well understood. To protect their work force, pharmaceutical companies establish internal OELs for their synthesis and product formulation activities. When seeking an OEL or exposure band for a hazardous drug, first check the manufacturer’s safety data sheet or inquire directly with a manufacturer. Alternatively, an OEL can be determined by a qualified occupational toxicologist.
SAMPLING STRATEGY Sampling strategy for hazardous drugs in controlled environments (which include pharmaceutical manufacturing and administration in healthcare settings) is different from uncontrolled environments (which include illicit cutting, manufacturing, transport, purchasing, and use of drugs).  In controlled environments, the presence and quantity of the hazardous drugs are known and the hazards understood; appropriate controls and work practices minimize potential exposure and risk. Therefore, the exposure assessment strategy, including sampling, is similar to IH sampling in other chemical processing industries. TWA and task- duration air sampling are performed to measure inhalation exposures and control effectiveness. Samples are collected by verified methods appropriate for hazardous drugs and submitted to an accredited laboratory for analysis. The sampling results are used to assess airborne concentrations against defined control or exposure limits.  In uncontrolled environments, the type, presence, and quantity of hazardous drugs may be suspected but unknown. Engineering controls are not available, so exposure risk is uncertain but potentially significant. Complicating this uncertainty is the fact that hazardous drugs have the potential to cause health effects even at airborne and surface concentrations too low to be visually detected. The drugs of concern in uncontrolled environments include extremely potent drugs of abuse such as synthetic opioids (fentanyl and related materials), which can be lethal in quantities as low as 2 to 3 milligrams. As a result, the purpose of sampling for hazardous drugs in uncontrolled environments is different than in controlled environments.  In uncontrolled environments, sampling is performed as an initial screening to confirm the presence and identity of hazardous drugs so that exposure control and remediation plans can be developed; to locate and isolate contamination for remediation or disposal; and to verify remediation efficacy and provide site clearance. Many aspects of the sampling strategy for uncontrolled environments are driven by a need for immediate qualitative feedback (as opposed to quantitative certainty) and an emphasis on surface residual testing over air sampling. The sampling strategy for hazardous drugs in uncontrolled environments will therefore include both qualitative, on-site field survey instruments where real-time results are needed (for initial screening and remediation feedback) and quantitative lab analysis of samples for assessment against clearance or health limits.  SAMPLING AND ANALYTICAL METHODS  As with exposure limits for drug products, development of the corresponding IH sampling and analytical methods is supported by the pharmaceutical companies. Sampling methods are developed by pharmaceutical companies or commercial labs. Pharmaceutical companies generally do not offer IH analytical services to third parties. The best place to identify available methods, get details on sampling and methods, and coordinate lab services is directly from the commercial industrial hygiene laboratories that provide these services to the pharmaceutical industry. A list of AIHA-accredited laboratories with capabilities for hazardous and highly potent drugs can be found using the search engine on the website of the AIHA Laboratory Accreditation Programs LLC (select the category “Pharmaceutical Testing”).  ANALYSIS TECHNOLOGIES The hazardous drugs with the highest potency have occupational limit values less than 1 µg/m3. Many drug manufacturing activities include short-duration tasks with heightened exposure risks, so measurement and assessment of task duration is necessary. These factors drive the need for extraordinarily sensitive sampling and analytical methods for hazardous drugs. To illustrate, measuring a drug that has an OEL of 1 µg/m3 to 10 percent of the OEL in a 15-minute, 30-liter air sample requires a method capable of quantitation at 3 nanograms per sample, which is well below the capabilities of the technologies used for typical industrial hygiene applications.  To address the sensitivity requirements, pharmaceutical IH laboratories employ a variety of high-powered technologies with analytical capabilities for both small- and large-molecule (protein and antibodies) hazardous drugs. These technologies include ultra-performance liquid chromatography (UPLC), enzyme-linked immunosorbent assay (ELISA), and liquid chromatography-tandem mass spectroscopy (LC/MS/MS). These techniques, LC/MS/MS in particular, provide highly selective and sensitive means to accurately quantitate hazardous drugs in complex matrices, even at nanogram-to-picogram mass loadings.  AIR SAMPLE COLLECTION Laboratory air sampling validation protocols performed to consensus pharmaceutical industry standards are typically as comprehensive and robust as OSHA and NIOSH methodologies. Most drug materials are handled and administered as solids or dissolved solids, with aerosol inhalation the primary concern for occupational exposures, particularly in manufacturing settings. As a result, the vast majority of air sampling methods for hazardous drugs employ filtration for sample collection. During media selection, a wide variety of filter substrate types are evaluated and employed for hazardous drug sampling, sometimes including chemical coatings to inhibit losses and improve collection efficiency. If drug vapors may be present or if potential sublimation from the filter during sampling is a concern, a sorbent component can be added to the sampling train behind the filter media.  SURFACE RESIDUAL SAMPLING IN CLINICAL SETTINGS In controlled pharmaceutical manufacturing environments, a significant amount of surface sampling for hazardous drugs is performed primarily to assess potential product- to-product cross contamination in multi-use facilities and equipment. Employee exposure risk in manufacturing is assessed primarily by air sampling. However, the analytical methods used in manufacturing hazardous drugs can be directly adapted to surface swab methods with appropriate validation.  In retail pharmacy compounding and healthcare clinical environments, surface residual sampling is the primary means of measuring hazardous drug contamination and assessing potential employee exposure risk, as specified in the pending USP chapter 800. Unlike air sampling, objective measurement of surface contamination can’t be compared directly to OELs for hazardous drugs. Surface contamination requires a subjective risk assessment of the potential for exposure based on a variety of factors, including the drug’s health effects rating, the surface from which the sample was obtained, the tasks conducted with the drug, and the engineering and work practices associated with the tasks. At present, there is no firm guidance on surface limits. Surface contamination values are a component of assessing risk, but they do not correlate directly to risk on their own. In short, what is found on a surface is not directly indicative of the potential risk to pharmacists or clinicians, though it is a component of such risk. Some considerations can assist with assessments in clinical settings. Positive results in a compounding or dispensing area are not unusual or unexpected. That said, a positive result in these areas is not insignificant and represents a potential source of drug transfer directly to people (via skin or eye contact or hand-to-mouth transfer) and objects (via shoes and cart wheels, for example). Test results provide information that can lead to procedural or housekeeping changes to improve control and reduce residual contamination—and, therefore, the potential for exposure. Positive results in unexpected areas outside of compounding or dispensing indicate migration of the drug away from the source, which warrants investigation into how it is occurring and how it may be mitigated. Procedural changes such as improvement in cleaning procedures or the use of shoe coverings or dedicated footwear may help control migration. This type of assessment is an example of how surface sampling with highly sensitive techniques provides value—it allows you to determine whether residuals are present even at low risk levels, so that improvements in procedures, controls, and housekeeping can be made to reduce the potential for a higher risk situation. SURFACE RESIDUAL SAMPLING IN UNCONTROLLED ENVIRONMENTS Highly potent drug materials should never be handled or administered outside of controlled or clinical environments. That said, the opioid epidemic and corresponding illicit drug trade have shifted the concern to fully uncontrolled environments—the Wild West, so to speak. The risks of occupational opioid exposure are primarily to first responders, law enforcement officers, and crime scene remediators. As with sampling in clinical environments, the focus is on identifying surface residuals. Unlike in clinical environments, immediate real-time sampling feedback is imperative for qualitative screening to identify the presence of the drugs and indicate the extent of contamination, moving the analysis from the laboratory into the field. A variety of qualitative analytical techniques and instruments are used; among the most popular is ion-mobility spectroscopy, which the U.S. Transportation Security Administration uses to screen for explosives at airports. For sampling that requires quantitative certainty for comparison to limits—for example, IH air samples or swabs to verify clearance—lab analysis is required.  RAPID IDENTIFICATION Controlling occupational exposures to hazardous drugs in uncontrolled environments is challenging due to the need to rapidly identify the drugs and the extent of the contamination so appropriate exposure controls can be implemented. The OELs and methods for sampling and analysis developed by the pharmaceutical industry, used in concert with qualitative analytical techniques, provide the IH with the tools to identify the presence of hazardous drugs and assess the potential for exposure so the appropriate controls, work practices, and PPE are used. The IH can also collect air samples during remediation activities and compare results to the pharmaceutical industry’s OELs to verify that appropriate controls have been implemented and create a historical record for future exposures. Semi-quantitative surface samples, analyzed in the laboratory, can also be obtained to assess the effectiveness of the remediation.  MATTHEW J. MEINERS, CIH, is consulting scientist at the Bureau Veritas Pharmaceutical Industrial Hygiene Laboratory in Lake Zurich, Ill. DONNA S. HEIDEL, CIH, FAIHA, is industrial hygiene practice leader at Apex Companies, LLC and treasurer of the AIHA Board of Directors. Send feedback to The Synergist.

mmg1design/Getty Images
Assessing Hazardous and Highly Potent Drug Exposures in Nontraditional Workplaces 

Sampling for Drugs in Uncontrolled Environments
Although the print version of The Synergist indicated The IAQ Investigator's Guide, 3rd edition, was already published, it isn't quite ready yet. We will be sure to let readers know when the Guide is available for purchase in the AIHA Marketplace.
My apologies for the error.
- Ed Rutkowski, Synergist editor
Disadvantages of being unacclimatized:
  • Readily show signs of heat stress when exposed to hot environments.
  • Difficulty replacing all of the water lost in sweat.
  • Failure to replace the water lost will slow or prevent acclimatization.
Benefits of acclimatization:
  • Increased sweating efficiency (earlier onset of sweating, greater sweat production, and reduced electrolyte loss in sweat).
  • Stabilization of the circulation.
  • Work is performed with lower core temperature and heart rate.
  • Increased skin blood flow at a given core temperature.
Acclimatization plan:
  • Gradually increase exposure time in hot environmental conditions over a period of 7 to 14 days.
  • For new workers, the schedule should be no more than 20% of the usual duration of work in the hot environment on day 1 and a no more than 20% increase on each additional day.
  • For workers who have had previous experience with the job, the acclimatization regimen should be no more than 50% of the usual duration of work in the hot environment on day 1, 60% on day 2, 80% on day 3, and 100% on day 4.
  • The time required for non–physically fit individuals to develop acclimatization is about 50% greater than for the physically fit.
Level of acclimatization:
  • Relative to the initial level of physical fitness and the total heat stress experienced by the individual.
Maintaining acclimatization:
  • Can be maintained for a few days of non-heat exposure.
  • Absence from work in the heat for a week or more results in a significant loss in the beneficial adaptations leading to an increase likelihood of acute dehydration, illness, or fatigue.
  • Can be regained in 2 to 3 days upon return to a hot job.
  • Appears to be better maintained by those who are physically fit.
  • Seasonal shifts in temperatures may result in difficulties.
  • Working in hot, humid environments provides adaptive benefits that also apply in hot, desert environments, and vice versa.
  • Air conditioning will not affect acclimatization.
Acclimatization in Workers