Sharks and Swimmers

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Sharks and Swimmers

Evaluating Hazard, Exposure, and Risk During OEL Selection and Use in the Pharmaceutical Industry

BY MICHAEL J. MCCOY, NADIA MOORE, AND CRAIG WILLEY

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Occupational toxicologists and industrial hygienists practice risk reduction techniques to control worker exposure in the chemical and pharmaceutical industries. They regularly face questions such as, “The Safety Data Sheet says that this product is a carcinogen; how are you going to protect me, and will I get cancer?” and “I know I’m exposed to this organic solvent; how do we decrease my exposure so I don’t get injured?” Answers to these questions are based within the interrelated concepts of hazard, exposure, and risk. While hazard refers to the specific harm an agent can inflict, the level of exposure (that is, concentration multiplied by time) is key for determining risk, or the likelihood the hazard will occur.

The example in Figure 1 provides an easily understood analogy of sharks and swimmers to explain these concepts to workers. The hazard component is represented by the harm of a shark bite; exposure occurs when the swimmer enters an ocean that contains sharks. Conceptually, workers should understand that in the absence of exposure (that is, if the swimmer is not in the ocean), there are no risks of adverse effects (that is, shark bites). Risk, or the likelihood of a shark bite, begins with oceanic swimming and changes with different types of sharks and exposure scenarios. Obviously, the industrial hygienist has the responsibility to anticipate, recognize, evaluate, and control other hazards associated with oceanic swimming and diving, such as jellyfish and “the bends.” For simplicity, we have focused on the shark as the hazard.

This example helps employees who, through their training on hazard communication, know to evaluate SDS for chemical hazards but are generally unfamiliar with the concepts of and interplay between risk and exposure. Sometimes, IHs struggle to communicate the true health risk to employees.

OCCUPATIONAL EXPOSURE LIMITS OELs are designed to protect nearly all workers from the risk of adverse effects when exposed over their working lifetime and can be used to help employees understand the health risks of compounds in the workplace. In Figure 1, the distance between the swimmer and shark in the ocean represents the OEL and its protective effect. Thus, the OEL provides sufficient distance to protect the swimmer from the risk of a shark bite. As explained in a 1997 paper in Occupational Medicine, occupational toxicologists establish OELs based on agent-specific doses (exposure levels), corresponding agent-specific adverse effects (hazards), and appropriate uncertainty factors that account for uncertainties in the toxicology database, in extrapolation of the selected dose level to the working human population, and other residual uncertainties. More recent publications, including a 2018 paper in Regulatory Toxicology and Pharmacology, have developed methods for risk assessment and OEL establishment for novel compounds, nanomaterials, and highly potent pharmaceutical compounds.

The process of selecting, reviewing, and using OELs is paramount, particularly in the pharmaceutical industry. Unlike medical contexts, most occupational exposures to pharmaceutical compounds occur via inhalation or dermal exposure. Exposure in the occupational pharmaceutical environment is rarely oral and very rarely via injection. If not well controlled, employees’ exposure to the product during the manufacturing process may be significantly higher in concentration and dissimilar to that of a person exposed to the drug for therapeutic purposes. With an understanding of the inherent hazards of the material, an IH working in concert with an occupational toxicologist can provide risk information to employees and develop appropriate controls at each step of the manufacturing process. As new toxicologic information is discovered, our knowledge of the hazard, its adverse health effects, and the risk of exposure may change. The key is understanding the differences between hazard, exposure, and risk, and controlling exposures through the correct establishment of OELs and proper controls.

Figure 1. A visualization of hazard, exposure, and risk. Image credit: Exponent.

Novel compounds are introduced into commerce frequently and are uniquely important for the development of a pharmaceutical pipeline. According to the U.S. Food and Drug Administration, in 2020, 53 new drugs were approved. In 2019, for example, the Chemical Abstract Service registered 1.4 million new chemical entities, not including novel compounds, which have only research and development purposes. The last decade has also included the development of highly toxic novel candidate pharmaceuticals, chemotherapeutics, and immune modulators, with OELs lower than one microgram per cubic meter.

When confronted with a novel compound to be used in the workplace, IHs can turn to several resources to ascertain whether an established OEL has been previously published by a regulatory body, agency, or trade group. Differences in OELs promulgated for the same compound generally stem from differences in selection of appropriate uncertainty factors or the underlying no-effect level.

Returning to the analogy of the shark and swimmer, a thoroughly vetted OEL will certainly provide us with the most current shark safety distances, based on the most current studies by shark marine biologists. However, if the shark data was based on outdated studies that overestimated or under-estimated the shark’s swimming speed, the OEL distance established for swimmers may be overprotective or under-protective. The same is true for OELs derived for compounds in active research, especially in the development and manufacturing of novel pharmaceutical compounds.

New pharmaceutical compounds arise from academic research and development labs and from worldwide pharmaceutical and chemical manufacturers. Early in the development process, toxicology data is often based on nothing more than the chemical family to which the compound belongs. If the compound is somewhat characterized, IHs and toxicologists may have access to information provided by the compound’s organic chemistry or its pharmaceutic or therapeutic family. In silico strategies such as quantitative structure activity relationship (QSAR) modeling can direct us to biological activities and potential toxicity for these compounds, but the accuracy of prediction varies with the compound, its biological target, and the maturity and validation state for the QSAR model used. Depending on the intended use for the new compound, early preclinical cellular and animal studies may be performed to help characterize toxicity during this phase of development. Toxicity data accumulate as the compound progresses through preclinical and clinical testing programs.

OELs for novel pharmaceuticals are often established by occupational toxicologists early in compound development, which is when the potential for occupational exposure begins, but before completion of most preclinical toxicity studies. Often in these cases an occupational exposure band (OEB) is established as an acceptable range of airborne concentrations. As the compound moves through the drug development process and toxicological data accumulates, the OEB evolves into an OEL. This process is illustrated in Figure 2.

Establishing OELs early in drug development may provide contract manufacturers adequate information to assess and control occupational risk, but it requires diligence on behalf of industrial hygienists to ensure the OELs reflect knowledge gained in the preclinical and clinical testing programs. Industrial hygienists have a duty to periodically monitor the appropriateness of the OELs we use to ensure they are not based on outdated studies or structure-activity relationships that may be overprotective or under-protective.

Figure 2. The toxicological evidence and basis for OELs evolves as time elapses and data accumulates. Image credit: Exponent.

Tap on the figure to open a larger version in your browser.

Regardless of industry, practicing industrial hygienists should regularly consult the toxicologic basis for the OELs they select to determine whether new information has surfaced and to think through the toxicity, mechanism, and health effects of the exposures they are measuring. This task is useful not only for conveying risk information to workers, but more importantly, it helps the industrial hygienist understand the state of the science and confirm that the selected OELs are accurate and applicable to the IH’s occupational environment. Ready examples of evolving OELs are the ACGIH Threshold Limit Values. The TLV book likely arrives every year at your home or office, and many industrial hygienists collect them for decades as markers of their years of service to the profession.

Novel pharmaceutical compounds may require significant research and additional review regarding mechanisms of toxicity and, ultimately, selection of an OEL, which often requires consultation with an occupational toxicologist. However, some compounds that lack typical OELs—such as TLVs, OSHA’s Permissible Exposure Limits, or the German Research Foundation’s MAK values—may have internal or company-specific OELs or banding criteria, which can be considered for use.

Table 1 lists some pharmaceutical compounds that have an established internal OEL and others that have an internal OEB. For the latter drugs, the banding scheme is based on occupational toxicity, with specific controls applied to each band. Also notable but perhaps not captured by the OEB is the inherent risk of exposure to penicillin G. According to the American Academy of Allergy and Immunology, approximately 10 percent of the U.S. population may be allergic to penicillin, a significant fraction that may include workers who handle the material. Unfortunately, many compounds that cause allergic reactions in workers do not follow typical dose-response relationships, and individual susceptibility can vary widely. As this example makes clear, industrial hygienists need to be aware of health risks perhaps not captured by the OEL. The possibility of such risks reinforces the need for a careful review of the basis for the established OEL.

Table 1. Examples of OELs and OEBs Available from Manufacturers*

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In the pharmaceutical industry, ongoing toxicologic reviews determine new information for establishing the OEL or adjusting the OEB. The OEL may need to be revised or changed throughout the lifecycle of a product, and this creates the opportunity for confusion. This confusion can arise from dated and unchanged banding schemes for a product or from assignment of a new band or OEL without proper hazard and risk communication. Revisiting our shark example, perhaps the original OEL was assigned based on the assumption that all sharks swim at the same speed, but subsequent studies have shown that our shark swims at a substantially slower speed, which means our OEL distance can be revised.

This article began with a discussion of the interplay between hazard, exposure, and risk and the importance of training workers to understand these concepts. Returning to the analogy of the shark and swimmer, simply identifying the hazard provides little information regarding the conditions that may impact the likelihood of the hazard to occur (such as swimming in the ocean with a large, bleeding wound). Similarly, a hazard that may be listed on an SDS represents no likelihood of occurring without exposure. Workers should understand that OELs are not thresholds above which harm occurs; instead, OELs represent the concentration to which nearly all workers can be exposed for their working lifetime without risk of harm. Any changes to OELs should occur through a transparent process, with the basis and impact for each change clearly conveyed.

VERIFY AND RECONCILE Industrial hygiene professionals, whether working in the pharmaceutical industry or in other sectors, should verify and reconcile OELs used within their organizations. These OELs should be reviewed for the compounds’ toxicity, mechanism of action (MOA), and applicability to the product formulation as well as their occupational use and ultimate risk. This review will ensure that chemists, chemical operators, and other drug manufacturing workers can conduct their important work producing pharmaceutical products for our collective health and wellbeing.

MICHAEL J. MCCOY, MS, CIH, DABT, is senior managing scientist at Exponent in Oakland, California.

NADIA MOORE, PhD, DABT, CIH, ERT, is vice president - principal toxicologist at J.S. Held LLC in Redmond, Washington.

CRAIG WILLEY, CIH, CSP, is corporate manager for Health and Chemical Hygiene at Cambrex in Charles City, Iowa.

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RESOURCES

American Academy of Allergy and Immunology: “Penicillin Allergy FAQ.”

FDA: “Novel Drug Approvals for 2020.”

Occupational Medicine: “Setting Occupational Exposure Limits for Pharmaceuticals,” (1997).

Regulatory Toxicology and Pharmacology: “Characterizing Risk Assessments for the Development of Occupational Exposure Limits for Engineered Nanomaterials” (June 2018).

Thoughtscapism: “Risk in Perspective: Hazard and Risk Are Critically Different Things” (Feb. 27, 2018).