Setting Occupational Exposure Limits for Chemical Allergens—Understanding the Challenges

Figures & data

Figure 1 Illustration of the development of allergic sensitization and diseases associated with chemical allergens. Illustration of a simplified description of the onset of allergic sensitization and diseases associated with chemical allergens. In the first phase, sensitization of a naïve individual occurs following an initial encounter with a chemical allergen that results in an adaptive immune response that primes the immune system for future exposures. This is a subclinical phase that is symptomless. Subsequent exposures to the chemical allergen trigger the clinical phase, referred to as elicitation, which manifests as allergic hypersensitivity reactions such as asthma, rhinitis, and allergic contact dermatitis.

Table 1 ACGIH Threshold Limit Values (TLVs) Based on Immune-mediated Health Endpoints^A

Chemical	CAS #	ACGIH
Beryllium and compounds	7440-41-7	TLV-TWA = 0.00005 mg/m^3 (as Beryllium, inhalable particulate matter); RSEN, DSEN
Flour dust	Not identified	TLV-TWA = 0.5 mg/m^3 (IVF); RSEN
Hexahydrophthalic anhydride	85-42-7; 13149-00-3; 14166-21-3	TLV-C = 0.005 mg/m^3 (IVF); RSEN
Hexamethylene diisocyanate	822-06-0	TLV-TWA = 0.005 ppm
Isophorone diisocyanate	4098-71-9	TLV-TWA = 0.005 ppm
Maleic anhydride	108-31-6	0.01 mg/m^3 (IVF); RSEN, DSEN
Methylene bisphenyl isocyanate	101-68-8	TLV-TWA = 0.005 ppm
Methylene bis(4,cyclohexylisocyante)	5124-30-1	TLV-TWA = 0.005 ppm
Natural rubber latex	9006-04-6	TLV-TWA = 0.0001 mg/m^3 (IVF); RSEN, DSEN, Skin
Piperazine	110-85-0	0.03 ppm ^(IVF); RSEN, DSEN
Toluene diisocyanate (TDI)
(mixture of 2,4-TDI and	584-84-9	TLV-TWA = 0.005 ppm;
2,6-TDI)	91-08-7	TLV-STEL = 0.02 ppm;SEN
Trimellitic anhydride	552-30-7	TLV-TWA = 0.0005 mg/m^3 (IVF); TLV-STEL = 0.002 mg/m^3; RSEN, DSEN, Skin

^ABased on ACGIH⁽¹⁰¹⁾ACGIH = American Conference of Governmental Industrial Hygienists; C = ceiling limit; CAS # = chemical abstract service number; DSEN = dermal sensitization notation; ^(IVF) = inhalable fraction and vapor; mg/m³ = milligrams per cubic meter; ppm = parts per million; RSEN = respiratory sensitization notation; skin = skin notation; STEL = short-term exposure limit; TLV = threshold limit value; TWA = time weighted average

Table 2 Overview of Animal Test Protocols Designed to Determine Skin Sensitization

Name	Protocol/Outcome
Modified Draize Test (MDT; mouse)^(^110^)	• The assay is conducted in two phases, induction and challenge. Induction phase is conducted by the administration of four intradermal injections in the shaven flanks; injection locations correspond with areas drained by specific lymph nodes. The challenge phase occurs on day 14. Intradermal injections at nonirritant concentrations are administrated. At 24 hr, skin responses are examined.
	• Skin responses to the challenge injection are graded and their size evaluated. Results are subjective in nature.
Buehler Test (guinea pig)^(^110^)	• The assay is conducted in two phases, induction and challenge. During the induction phase, one to three weekly occlusive topical applications of the test substance at slightly to moderately irritating concentrations are applied to shaven patches on the shoulder of animals. This occurs for 3—9 weeks. Fourteen days after the last induction exposure is conducted, the challenge phase begins. Nonirritating concentrations of the test substance are applied topically to a naïve shaven site and covered for 6 hr.
	• Skin responses are examined and graded on a scale similar to the one used in the MDT. Evaluation of the graded skin response is based on two parameters. The first parameter, called the incidence index, refers to the percentage of animals that responded positively to the challenge phase. The second parameter, called the severity index, provides an estimate of the total sum of reactions grades divided by the number of exposed test animals.
Guinea-pig Maximization Test (GPMT; guinea pig)^(^111^)	• Procedure designed to subjectively screen the allergenicity potential of test substances. The assay is conducted in two phases, induction and challenge. Induction is conducted in two distinct stages. In stage 1, animals receive paired intradermal injections in the shaved shoulder region along with and adjuvant to boost the potential immune response on day 1. In stage 2, animals receive a topical occlusive patch containing the test substance applied to the shaved shoulder region on day 7; this patch is removed 48 hr after application. Challenge is performed on day 21 by the topical application of a nonirritating concentration of the test substance on an occluded naïve site on the flank of test animals for 24 hr. Responses are evaluated at 24 hr and 48 hr after challenge dose is applied.
	• Skin responses are graded with a standard rating scale that allows for the standardized classification of allergenic potential. Score assigned ranges from none to extreme responses.
Mouse Ear Swelling Test (MEST; mouse)^(^110^)	• Procedure designed to quantitatively measure mouse ear thickness as an indication of allergic response. The assay is conducted in two phases, induction and challenge. Induction is conducted in two distinct stages. In phase 1, test animals are pretreated with an intradermal injection in the shaved abdomen. Topical application of the test substance occurs for 3 consecutive days at the site of the injection. The challenge phase begins on day 10 after a 1-week recovery period with the topical application of a lower concentration of the test substance to one ear, while a vehicle is placed on the opposing ear. Ear thickness measurements are taken at 24 hr and 48 hr post topical application.
	• If the increased ear thickness of one or more test animals is 20% greater than the thickness of the controls’ ears, then the test substance is identified as a sensitizer. Potency of the sensitizer is based on both the increased ear thickness and number of animals with positive responses.
Murine Local Lymph Node Assay (LLNA; mouse)^(^110^)	• Procedure capable of determining the relative allergenic potency of a test substance. Animals are treated topically with the test substance at a selected concentration for 3 consecutive days. Five days after the first treatment, test animals receive an injection of a radiolabelled chemical that is incorporated within lymphocytes contained within the lymph nodes draining the sites of exposure.
	• Measurement of the proliferation of lymphocytes provides a quantitative estimate of sensitization potential. Results are reported as Stimulation Index (SI), which refers to a comparison of the net increase of lymphocytes or proliferation rate within test animals compared to controls. Skin sensitizers are identified as chemicals that are able to induce an SI of 3 or greater (i.e., a 3 times or greater response in test animals as compared to controls) at a given concentration.

Table 3 Qualitative Hazard Notations Designations for Chemical Allergens

Organization	Designation	Definition	Reference
ACGIH	SEN	• Potential for an agent to produce sensitization, as confirmed by human or animal data; may refer to dermal and/or inhalation sensitization	ACGIH^(^101^)
	RSEN	• Respiratory sensitization notation - used in place of the SEN notation when specific evidence of sensitization by the respiratory route; does not imply that sensitization is the critical effect on which the TLV is based
	DSEN	• Dermal sensitization notation used in place of the SEN notation when specific evidence of sensitization by the dermal route; does not imply that sensitization is the critical effect on which the TLV is based
CAL/OSH	“D” SEN	• Substances can cause occupational dermal sensitization responses even when exposures do not exceed the values (i.e., PEL)	CAL/OSHA^(^112^)
	“R” SEN	• Substances can cause respiratory sensitization
GHS	Hazard statement 317	• May cause an allergic skin reaction	UNECE^(^100^); EC^(^113^)*
	Skin sensitizer – Category 1	• Substance causes skin sensitization within humans or animals
	Hazard statement 334*	• May cause allergy or asthma symptoms or breathing difficulties if inhaled
	Respiratory sensitizer – Category 1	• Substance causes respiratory sensitization within humans or animals
NIOSH	SEN	• Potential for immune-mediated reactions following exposure(s) of the skin	NIOSH^(^98^)

ACGIH = American Conference of Governmental Industrial Hygienists; CA OSHA = California Occupational Safety and Health Administration; GHS = Globally Harmonized System for the Classification and Labeling of Chemicals; DSEN = dermal sensitization; PEL = permissible exposure limit; RSEN = respiratory sensitization; SEN = sensitization

Table 4 Risk Management Guidance for Chemical Allergens

Control Technique	Specific Control	Areas of Increased Emphasis in Allergen Risk Management
Substitution	Molecular substitution	• Replace chemical allergen with alternative non-allergenic molecule
		• Encapsulate or modify chemical at the molecular level to reduce access to allergenic moiety
Engineering	Process Design	• Limit the use of chemical allergen at latest possible phase in process to minimize the potential duration of exposure and the need for engineering controls
		• Select equipment and processes that minimize aerosol generation of LMW chemical allergen
		• Develop plan for spill containment of LMW chemical allergen
	Isolation	• Enclose operations where chemical allergens are added, used, stored, or disposed
	Ventilation	• Local exhaust ventilation (LEV) should be used in areas where chemical allergens are added into the process, stored, or disposed
		• Maintain equipment at a negative pressure to ensure inward flow of air to prevent escape of LMW chemical allergen
		• Dilution ventilation should be used to supplement LEV
Administration	Work-practice	• Management systems should be developed to main hygiene standards within the workplace
		• Operational controls should be put in place to achieve no visible dust, no recurring spills, no gross skin contact, and prevention of aerosol generation
		• Worker education program should include an overview of the health effects of LMW chemical allergens, use of controls, safe work practices, and contingency measures for spills or releases of the LMW chemical allergens
		• Access to high risk activities and locations should be restricted
		• Safe work practices should be established that provide guidance on good personal and workplace hygiene, storage, use, and disposal of LMW chemical allergens, and clean-up of spills
	Medical monitoring	• Medical monitoring should be conducted for workers potentially exposed to LMW chemical allergens to assess and monitor their health. Programs should attempt to identify workers who have early or pre-clinical work-related allergy/asthma
		• Symptom questionnaires are an essential component of medical surveillance of such workers, in addition to tests for sensitization and exposure biomarkers, where available
	Exposure monitoring	• Exposure monitoring should be conducted to validate the efficacy of engineering controls, ensure airborne concentrations are maintained below OELs, hazard banding range, or other exposure recommendations
		• Exposure monitoring should focus on both air and surface contaminant (wipe and skin) sampling
Personal Protective Equipment (PPE)	PPE program	• Programs should emphasis the use of respiratory and skin PPE capable of protecting workers from the specific chemical allergen
		• Use of PPE should be directly coupled with engineering and administrative controls
		• PPE reuse should be limited to prevent secondary exposures; if reused, decontamination protocols should be established
		• Workers should be educated on the use and decontamination of PPE

Table 5 Checklist Summary of Key Considerations During Assessment of Health Risks Associated with Chemical Allergens

Critical Question(s)
Is there an allergen risk for this task/workplace?
Is the chemical an allergen?
▪ What guidelines are available (i.e., OELs, hazard notations)?
▪ What data are available (i.e., epidemiology, animal, in vitro)?
▪ How can data be integrated?
What are the exposure levels within the workplace?
▪ What exposure pathways are important?
▪ What are the temporal patterns (i.e., acute [peak] exposure vs. full shift exposure)?
▪ What physical forms (particulates, gases/vapors) are important?
For the task/workplace, is there an allergen risk? If so, what is the severity of the risk?
▪ Are data capable of deriving an OEL?
▪ Are data capable of assigning a hazard band?
▪ Are data capable of assigning a hazard notation?
What control strategies are needed to mitigate the risk?
▪ Manage to prevent sensitization?
▪ Manage to prevent elicitation?
Strategy for communicating in place?

Figure 2 Consideration in assessing the health risks of potential chemical allergens. HB = hazard band; OEL = occupational exposure limit; WOE = weight of evidence.Theflowchart illustrates key consideration during the risk assessment of potential chemical allergens. On the basis of the risk assessment paradigm, the outlined process relies on a weight of evidence approach to critically evaluate available data. Included within the flowchart are options within each of the primary steps: hazard characterization, dose-response analysis, exposure assessment, risk characterization, and risk management and communication. These options allow for the evaluation of data, determining appropriate level of recommendation developed (i.e., hazard notation vs. occupational exposure limit), type of exposure assessment, and control technique.

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