Skin sensitization is one of the most frequently encountered hazards in the workplace, yet one of the most perplexing to predict and prevent. This occupational hazard can have significant consequences within and outside of the working environment. If sensitized, workers may be required to avoid being exposed again to a distinct compound or a class of chemicals by changing jobs or rotating to another building; they may also need to attenuate the effects of the immune system’s response with medications or refrain from using various products at home (such as products for do-it-yourself projects or hobbies like automobile maintenance). 

In the occupational environment, many efforts are made to identify potential skin sensitizers used in production through available testing and proper risk and hazard communication. Unfortunately, despite these efforts, this toxicological endpoint remains a qualitative assessment, with the resulting conclusion that industrial hygiene procedures should focus on reducing peak exposures. But what does this qualitative assessment entail? How does the toxicological characterization take place? Why is it so difficult to predict if an individual will react with a skin sensitization, and how can sensitization be prevented? How should workers protect their skin? How can workers identify a reaction, and what should they do if they experience one? Why hasn’t industry already adopted a standard approach to handling sensitizers? In this article, we provide a brief overview of the industry approach where dose-related reactions can be highly variable among individual workers. 
WHERE SENSITIZERS ARE FOUND The OSHA Hazard Communication Standard, or HCS, defines a sensitizer as “a chemical that causes a substantial proportion of exposed people or animals to develop an allergic reaction in normal tissue after repeated exposure to the chemical” (emphasis added). Sensitizers are present environmentally and occupationally in many different industries including pharmaceuticals, chemical production, biofuels, and food and beverage; they are also in many consumer products. According to Anton C. De Groot’s book Patch Testing, more than 4,300 substances are identified as contact allergens, which are usually small molecules. Epidemiological studies published in the Journal of Dermatology (in 2016) and Contact Dermatitis (2019) suggest that the prevalence toward developing a skin sensitization or positive allergic contact dermatitis (ACD) in the global population is about twenty percent. Approximately half of occupational ACD cases are due to rubber, nickel, and fragrances. The rest come from preservatives, cosmetics, chromate, aromatic amines, and epoxy and other resins. Well-known examples of sensitizers are toluene diisocyanate, nickel compounds, and poison ivy.  THE TOXICOLOGY BEHIND SKIN SENSITIZERS  In the occupational environment, a sensitized worker who has been exposed to a skin sensitizer presents, after exposure, symptoms of contact dermatitis or eczema and, on rare occasions, mucositis. As these effects are also present following an irritative type of reaction, called irritative contact dermatitis (ICD), it is important to differentiate ICD from ACD. Unlike ICD, ACD often presents outside a confined skin area that has been exposed to the substance, can be stronger with further exposures, and can take place after exposure to a low amount of the substance. Another difference, as explained in a 2008 study published in Allergy, Asthma & Clinical Immunology, is that the onset of ACD is delayed 12 to 48 hours (the delay is necessary for activation of the immune cells and the proliferation process).  ACD can be conclusively diagnosed only with a Human Repeated Insult Patch Test (HRIPT, also known as “prick tests”). However, the HRIPT can itself lead to sensitization and is therefore not preferred to confirm a diagnosis. Moreover, repeated testing might be required in order to correctly identify the sensitizer from multiple possibilities.  According to the OSHA HCS, a sensitizer (allergen) causes little or no reaction in humans or test animals on first exposure. The problem arises on subsequent exposures, when a marked immunological response occurs, because the immune system already knows the dermal allergen. Therefore, there are two potential thresholds for skin sensitization: at the induction and elicitation phases (see Figure 1). Induction is defined as the tolerance of the exposure by the immune system, whereas elicitation is the reaction from a sensitized person. Moreover, elicitation can become stronger with repeat exposures, which further decreases the threshold.
Allergy, Asthma & Clinical Immunology:Occupational Contact Dermatitis” (2008). Contact Dermatitis: “Prevalence of Contact Allergy in the General Population: A Systematic Review and Meta-analysis” (February 2019).  Cosmetics: “Safety Evaluation of Cosmetic Ingredients Regarding Their Skin Sensitization Potential,” Figure 1 (March 2016). Journal of Dermatology: “Prevalence of Contact Allergy in the General Population in Different European Regions” (February 2016). OSHA: “Guidance for Hazard Determination for Compliance with the OSHA Hazard Communication Standard.” Wapserveen: Patch Testing: Test Concentrations and Vehicles for 4350 Chemicals, 3rd edition (2008).

Figure 1. The exposure required for induction and elicitation of skin sensitization can differ by orders of magnitude.
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Figure 2. Schematic representation of how skin sensitization takes place. Adapted from “Safety Evaluation of Cosmetic Ingredients Regarding Their Skin Sensitization Potential,” Figure 1, by Winfried Steiling, Cosmetics (March 2016).
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Many parameters affect dermal sensitization. Some include the duration and intensity of exposure, chemical properties, and of course, individual susceptibility. However, a type IV immune reaction is the true cause of dermal sensitization. As illustrated in Figure 2, the immune cells keratinocytes, Langerhans cells, and T lymphocytes play a crucial role. First, a chemical with dermal sensitization potential has to be able to penetrate into the skin—meaning it must have a low molecular weight, usually less than one kilodalton—and induce or elicit an immune response by being chemically reactive and electrophilic with skin proteins. (These proteins are dermal sensitizers, but they are too small to be allergenic. They have to bind to a protein to be allergenic.) Subsequently, keratinocytes are stimulated by the allergen and release immune mediators, which induce Langerhans cells to migrate and activate memory T cells in the lymph nodes by presenting them the antigen. T cells then proliferate and are ready to elicit a stronger immune reaction whenever the next exposure to the same chemical occurs.
Toxicity tests in vivo used to predict potential sensitizers are the Guinea Pig Maximization Test (GPMT); the Buehler assay in guinea pigs, where a patch clamp is used followed by visual scoring (similar to the HRIPT in humans); and the Mouse Local Lymph Node Assay (LLNA), where stimulation of T cells is characterized by quantifying their amount in the lymph nodes. LLNA, which was designated as a standalone test by the Organization for Economic Cooperation and Development in 2001 and by the European Union in 2002 following extensive national and international validations, still represents the gold standard in vivo test. Two advantages of LLNA compared to the other skin sensitization tests are that it allows an assessment based on potency represented by “EC3” values (a concentration at which a stimulation index of the immune response following elicitation is greater than three), and it is better in terms of animal welfare by decreasing testing times, number of animals, and discomfort with the patch clamp during the elicitation phase of the immune response. To further support a decrease in animal use, research is being conducted to determine new methods of predicting sensitization potential while avoiding the use of animals for testing; examples include in chemico/in vitro methods. Some of these assays are now accepted, but their advantages are currently limited to a “yes or no” identification of skin sensitizers. SENSITIZATION: AN EXAMPLE  Differentiating between a case of ACD or ICD in production can be very difficult for hygienists because we aren’t exactly chemists, toxicologists, or medical practitioners. But we must have enough knowledge from all of these fields to know which questions to ask.  It is important to conduct a thorough investigation and understand from where potential exposures could come. Particular attention should be paid to chemicals where skin sensitization tests are not available and where potential risk cannot be anticipated. Many cases occur from products that aren’t even classified as sensitizers—for example, a worker who exhibits symptoms during steps in the process where no concrete hazard phrase or warning existed. Unfortunately, this often happens with products such as intermediates, which do not come with a full data package and are not classified as sensitizers.  Some cases are very clear because the worker exhibits symptoms of dermatitis immediately upon entering the production area or building where the product is used, every time the worker is exposed to the substance. These symptoms disappear when the employee returns home for an extended period or goes on vacation and reappear when the employee reenters the workplace. When local effects are exhibited, distinguishing between irritation and sensitization is sometimes difficult. The key difference is where the symptoms are present on the body and whether delayed reactions occur. The response may be a generalized body condition, not necessarily limited to the contact site. Signs of ICD include subacute or chronic eczema with desquamation (peeling) or fissures, while signs of ACD include acute to subacute eczema with vesiculation (blistering).  HOW TO HANDLE SENSITIZING AGENTS Presently there is no generally applicable method to calculate workplace exposure threshold concentrations for skin sensitization, especially because the preclinical data is from a dermally applied concentration and OELs are generally calculated for the inhalation route of exposure.  Different companies have integrated different methods or mindsets for handling sensitizers in production. Company solutions regarding sensitizers can be individually tailored and therefore not necessarily applicable across all industries. Where the company decides to set its limits also depends upon the acceptable percentage of sensitized individuals. 
Table 1. Dermal Sensitizers: Pharma Industry Benchmarking
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A benchmarking summary of how companies consider skin sensitization potential in the pharmaceutical industry appears in Table 1. Companies A, B, and C directly integrate the sensitization hazard into the exposure limit or occupational exposure band. In contrast, companies D, E, F, and G either include a sensitization or skin notation on the OEB (without including it in the OEL calculation) or directly calculate surface limits instead of considering it via the inhalation route.  Many companies, especially in the chemical and pharmaceutical industry, have integrated the sensitization aspect into hazard or control banding systems (similar to Companies A, B, and C in Table 1). In that case, a higher level of containment is automatically required, as the sensitizing products are placed in a band with a range of very low exposure limits. Some may even be considered highly potent compounds, with OELs of less than 10 µg/m3. But in some industries, using costly high level containment can impose great constraints on production and is not really a feasible option. This has been our experience in the agrochemical and cosmetics industries, where lower margins on products result in lower investment in controls. In these industries, the choice of protective measures easily becomes personal protective equipment. The problem with this solution is of course that the PPE needs to be removed at some point and the risk of skin contact or inhalation from a suit contaminated with product still remains. Therefore, the only true way to reduce the risk is containment of the process.  It is also possible to simply use the hazard phrases or skin notations to alert occupational health and safety professionals to the need for special measures during the risk assessment. (This is the approach favored by Companies E, F, and G in Table 1.) In this case, one would consider using a higher level of containment regardless of the OEL value. Theoretically, relying on hazard phrases in this manner is appropriate only when the hazard phrases have been validated. In practice, many field practitioners do not have an in-house toxicologist to validate hazard information for all products, and most EHS professionals must make decisions based on the data they have available. Because the quality as well as quantity of available data can drastically vary, the following indications may help to gauge the reliability of your data. Hazard phrases present on a safety data sheet are generally more conservative and less reliable; they could be validated by looking at positive toxicity studies publicly available in the European Chemical Agency’s database of registered substances or obtained by the compound’s supplier. Alternatively, even stronger supporting data come from epidemiology; in the case of a commercial active pharmaceutical ingredient, sensitization reactions could be listed in the labelling information under adverse events noted in the clinical or post-marketing authorization phases. Nevertheless, based on reliable epidemiological data, the sensitization risk may be included in the calculation of OELs; in cases where a high frequency of people exhibit sensitization reactions, the OEL can be decreased with a qualitative adjustment. A good example is beta lactams (a type of antibiotic drug). Beta lactams are used clinically at high doses, which would lead to a rather high OEL value when considering the clinical dose in the OEL calculation. A qualitative OEL adjustment could help to avoid cases of sensitization in the production of beta lactams by reducing the OEL and therefore requiring a more rigorous risk assessment in some companies.  In summary, because of the variability of the toxicity data available to identify skin sensitizers, the inability to identify a general induction/elicitation threshold in workers, and industry’s broad strategy of communicating (validated) skin sensitization potential with differential approaches (exposure banding, surface target values, GHS hazard or skin notation statements), dermal sensitization should be considered as a qualitative assessment and peak exposures should be avoided. For this reason, it is important for the IH practitioner to consider the company’s chosen strategy for identifying potential skin sensitizers when developing a containment strategy and selecting PPE at the workplace. OTHER CONSIDERATIONS FOR THE IH PRACTITIONER  Of course, the number one goal for any health and safety specialist is to prevent exposure as much as possible. When considering the hierarchy of controls, this would mean either substituting for a non-sensitizing product or using technical controls to contain the product as much as possible.  Nevertheless, there are several important points that should be considered: Remember to assess all potential routes of exposure. Do not forget to evaluate the potential for dermal contact. What could be the potential concentration of product on the skin, and how easily could it be absorbed? Air sampling results do not directly relate to surface contamination. This is a crucial point for the exposure assessment when working with dermal sensitizers. Even if air sampling results are very low, it is important to consider where else the worker may come into contact with the product. For example, in the case of powder handling, was the surrounding area cleaned well between the batches or campaigns? Does the next worker risk being exposed when turning a knob or handle or using the same tools as another worker? Surface monitoring, or “wipe samples,” can be used to answer these questions.  Dermal contact can also occur via cross- contamination of areas or services that aren’t directly related. If someone from maintenance is using improperly decontaminated tools from production, they too might risk being exposed.  Peak exposures should be avoided, regardless of the OEL. Concentration of the product on the skin is more important than the surface area covered.  Other special considerations during the risk assessment include the use of surfactants in the process or requirements for wet work or handling of aggressive chemicals (such as caustics), which can break the skin’s barrier. Surfactants, for example, can reduce the effective limits three to ten times lower than usual, according to the 2016 study in the Journal of Dermatology.  Sometimes products are not classified as sensitizers, and unfortunately, the first cases are seen without warning in production. When this happens, it is essential to alert the internal toxicologist or regulatory specialist by reporting potential or confirmed sensitization cases to management and to conduct an investigation regarding the employees’ potential exposures from work and home. Such an investigation should consider whether the employee uses soaps with fragrances or known sensitizing agents (at work or at home) or wears powdered gloves (the employee could be allergic to the powder or glove material). When multiple cases of confirmed skin sensitization are reported, a more stringent containment strategy to decrease employee exposure to the compound must be considered.   SAMANTHA CONNELL, MSPH, CIH, is an industrial hygienist at Lonza in Visp, Switzerland. SELENE ARAYA, PhD, is a toxicologist at Lonza in Basel, Switzerland. Acknowledgment: The authors would like to thank Ester Lovsin Barle, PhD, MScTox, ERT, for her contribution of industry research. Send feedback to The Synergist.

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What Does Our Immune System Already Know?
Dermal Sensitizers
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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