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PreventionofLaboratoryAnimalAllergy
Gregg M. Stave, MD, JD, MPH13th CDC International Symposium on BiosafetyJanuary 27, 2014
QuestionsWhy do people develop LAA? Is it possible to predict who will develop LAA? Does exposure to allergens vary by job or task? Are some animals more likely to cause LAA?When hiring new employees, should people with LAA be excluded? If someone doesn’t develop LAA within 3 years, are they unlikely to develop LAA?
Questions● Can LAA be prevented?●What are the elements of a comprehensive approach to preventing LAA?● Is there an Occupational Exposure Level (OEL) to prevent LAA? ● Are respirators really necessary to prevent LAA? ●What should be included in a medical surveillance program for LAA?● Should workers with LAA be excluded or restricted from work?
LaboratoryAnimalAllergy(LAA) Laboratory animal workers are at risk of developing occupational allergy and asthma
LAA can adversely affect personal health and career options
LAAisCommon In the medical literature: Between 10 and 44% of people working with laboratory animals have respiratory allergy Up to 17% of those with allergy develop asthma Asthma can progress even in the absence of continuing exposure
CausesofLAA LAA is triggered by protein allergensDanderHairSalivaUrine
Allergens are also present in bedding, and on cages and other work surfaces
MechanismofLAAProtein allergen inhaled
Activate T helper cells
Stimulate B cells
Produce IgE antibodies
ImmunologyofAnimalAllergy Human Leukocyte Antigen (HLA) /MHCHLA class II molecules are involved in the presentation of allergen to the T cell HLA‐DR7 was associated with sensitization (odds ratio [OR], 1.82; CI, 1.12‐2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64‐5.37) and, most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90‐7.65) HLA‐DR3 was protective against sensitization (OR, 0.55; CI, 0.31‐0.97)
Jeal H et al. HLA associations with occupational sensitization to rat lipocalin allergens: A model for other animal allergies? J Allergy Clin Immunol. 2003 Apr;111(4):795‐799.
ImmunologyofAnimalAllergy High levels of allergen‐specific IgG have been associated with clinical efficacy in immunotherapy studies Among workers with detectable mouse IgE, higher mouse IgG and mouse IgG4 levels are associated with a decreased risk of mouse‐related symptoms
Matsui EC, et al. Mouse allergen‐specific immunoglobulin G and immunoglobulin G4 and allergic symptoms in immunoglobulin E‐sensitized laboratory animal workers. Clin Exp Allergy. 2005 Oct;35(10):1347‐1353.
PossibleProtectiveFactors• Early‐life exposure to dogs is protective against allergic disease development • Dog ownership is associated with a distinct milieu of house dust microbial exposures • Mice exposed to dog‐associated house dust are protected against airway allergen challenge:• reduced Th2 cytokine production, • fewer activated T cells, • distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii, which itself can confer airway protection when orally supplemented as a single species
Fujimura et al., House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defenseagainst allergens and virus infection. PNAS December 2013 www.pnas.org/cgi/doi/10.1073/pnas.1310750111
Glaxo LAAProgram
Program instituted to decrease incidence of LAA (1991) Involved scientists and technicians working with animals
Goodno LE, Stave GM. Primary and secondary allergies to laboratory animals. J Occup Environ Med. 2002 Dec;44(12):1143‐1152.
ProgramEvaluation
Medical surveillance data collected for ten years (1/91 ‐ 12/00)Medical history LAA questionnaire RAST (IgE) OSHA log
SpeciesSpecificExposuresandSymptoms
Goodno LE, Stave GM. Primary and secondary allergies to laboratory animals. J Occup Environ Med. 2002 Dec;44(12):1143-1152.
SurvivalCurvesFirstandSecondAllergies
Goodno LE, Stave GM. Primary and secondary allergies to laboratory animals. J Occup Environ Med. 2002 Dec;44(12):1143‐1152.
SecondaryAllergy Once a worker develops animal allergy, the risk of developing allergies to additional species is high This risk is present in an environment that is protective against development of primary allergyWorkers should be counseled regarding this risk
Under the Americans with Disabilities Act (ADA) and the Americans with Disabilities Amendment Act (ADAAA), employers are prohibited from asking about medical conditions prior to making a job offer Employers also have a general requirement to make the workplace safe for all New employees hired to work with laboratory animals, or employees transferred to animal work, should participate in a post‐offer pre‐placement assessment to address any concerns regarding work with animals
There are several published reports that suggest that primary LAA commonly develops within three years of beginning employment However, LAA can develop at any time, so it should not be assumed that LAA could not develop after this time Secondary LAA may develop many years after primary LAA
PreventingLAA
Prevention of LAA requires reduction of exposure to allergens
Methods to control exposure:EnvironmentalAdministrativeWork Practice Personal Protective Equipment
EnvironmentalControls
Negative pressure environments Local exhaust ventilation Ventilated equipment Filter‐topped cages Down draft tables
ScientificConsiderationsinCageSelection
• Individually ventilated cages (4 mice per cage)• Chronic low‐grade hypoxia (O2 21%20.5%)• Increased red cells and platelets, decreased white cells• Increased saccharin preference and fluid consumption
York et al. Individually ventilated cages cause chronic low-grade hypoxia impacting mice hematologically and behaviorally. Brain, Behavior, and Immunity 26 (2012) 951–958
AdministrativeControls Minimize animal use to extent feasible Training and education of workers Restricted access to animal rooms Limit animal use to the animal facility Restrict contaminated PPE to animal
facility
WorkPracticeControls Limiting animal density Work process design to reduce animal
handling Wet prep for shaving Room cleaning procedures that minimize
exposure Hand washing
PersonalProtectiveEquipment
Respirators Gloves Shoe covers Hair covers
Protective clothing Lab Coats Gowns Tyvek
HairNetscanPreventTransferofAllergens
Family members of laboratory animal workers are at risk of developing allergy to laboratory animals Occupational laboratory animal allergens are detectable in mattress dust of laboratory animal workers Transfer of allergens via uncovered hair of animal workers is likely contributing to this phenomenon
Krop EJ, et al. Spreading of occupational allergens: laboratory animal allergens on hair‐covering caps and in mattress dust of laboratory animal workers. Occup Environ Med. 2007 Apr;64(4):267‐272.
NationalSurveyofLAAPreventionPractices● An online survey was e‐mailed to the designated institutional official at all laboratory animal care facilities identified by the NIH Office of Laboratory Animal Welfare (approximately 1000 facilities across the country)
●The study protocol was approved by the Duke Institutional Review Board
● Responses received from 198 organizations
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Category of Institution Percent Number
University/Academic/Medical Center
68.7 136
Research Institute 15.2 30
Pharmaceutical 7.0 14
Other Commercial 7.1 14
Other 2.0 4
Total 198
Distribution of survey respondents by type of institution
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Number of Employees working with animals
Percent
<15 14.7
15‐99 38.9
100‐499 25.8
500+ 20.5
Distribution of survey respondents by size of workforce
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Engineering Controls Percent
Robotic equipment 7.1
Separately ventilated caging 64.5
Biological Safety Cabinets 74.1
Local Exhaust ventilation 76.6
Negative pressure environments 74.6
Filter top cages 75.6
Downdraft tables 37.1
None 3.0
Engineering controls used to reduce exposure to animal allergens
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Administrative Controls Percent
Training of workers on LAA prevention 81.6Restricting access to animal rooms 92.3Limiting animal use to animal facilities 47.4Restricting contaminated/used PPE to animal facility
80.6
Shower out 20.4Separate lockers for clean clothes 48.0None 1.0
Administrative controls used to reduce exposure to animal allergens
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Work Practice Controls Percent
Limiting animal density 65.3
Work process design to reduce animal handling
55.1
Wet prep for shaving 19.9
Room cleaning procedures that minimize exposure (HEPA filter vacuum, wet process, etc.)
66.3
Hand washing 96.4
None 0
Work practice controls used to reduce exposure to animal allergens
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Mandatory (always required for animal work) Personal Protective Equipment (PPE)
Percent
N95 air purifying respirators 16.6Cartridge air purifying respirators 2.6Powered air purifying respirators (PAPRs) 6.1Surgical masks* 42.9Shoe covers 52.6Uniforms/clothing cover 85.7Hair covers 37.8Gloves 88.3None 4.6
Mandatory personal protective equipment used to reduce exposure to animal allergens
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Optional (available, not required) Personal Protective Equipment (PPE)
Percent
N95 air purifying respirators 63.0Cartridge air purifying respirators 25.5
Powered air purifying respirators (PAPRs) 34.8
Surgical masks* 54.3Shoe covers 41.8Uniforms/clothing cover 28.3Hair covers 40.2Gloves 30.4None 7.1
Optional personal protective equipment used to reduce exposure to animal allergens
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Mandatory Personal Protective Equipment (PPE) required only for specific tasks:
Cage cleaning
Cage Washing
Animal Care
Dosing Surgery Necropsy
N95 air purifying respirators 24.7 16.8 15.8 8.4 7.9 6.3
Cartridge air purifying respirators
3.7 4.7 2.1 2.1 1.1 0.5
Powered air purifying respirators (PAPRs)
5.8 4.7 3.7 2.6 2.6 3.7
Surgical masks* 36.3 31.0 40.0 32.1 64.2 39.5
Shoe covers 48.4 44.7 50.5 43.7 48.4 43.2
Uniforms/clothing cover 83.2 80.0 83.7 73.2 76.8 78.4
Hair covers 85.8 32.6 39.5 82.6 42.1 31.1
Gloves 85.8 80.5 86.3 82.6 86.3 86.3
None 2.6 2.6 2.6 3.7 2.8 3.2
Mandatory personal protective equipment required for specific tasks
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
• OELs are set for adverse health effects, but not sensitization• Animal allergens are respiratory sensitizers• Based on available evidence, a working level to reduce the risk of sensitization is probably in the range of a few ng/m3
Exposure prevention is necessary If exposure cannot be adequately controlled with other methods, then respirators are needed This is likely to be the case in the vast majority of workplaces today In the only published program that successfully prevented the development of primary animal allergy, mandatory respirator use was a component of the comprehensive program
There is no specific OSHA standard that addresses LAA, as OSHA standards tend to address physical and chemical, but not biological hazards (the bloodborne pathogen standard is one notable exception) However, LAA is a significant occupational hazard that requires medical surveillance
Medical surveillance should begin with a pre‐placement assessment to identify risk factors and existing LAAPeriodic individual assessments, usually annual, should be used to identify previously undiagnosed LAA Data from these surveillance assessments should be periodically analyzed to look for trends. This process is known as group surveillance In addition, workers should be encouraged to have an occupational medical evaluation if they have any symptoms that may represent LAA
Medical Surveillance for LAA is: Percent
Mandatory for all 58.1
Mandatory for some 14.1
Voluntary for all 11.5
Voluntary for some 0.5
Not conducted 15.7
Medical surveillance policies of respondents
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Medical surveillance for LAA is more likely to be conducted by organizations with larger animal research workforces
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Medical surveillance practices by type of organization
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Medical Surveillance for LAA includes:
Percent
Questionnaires 91
Clinical Exam 52.1
RAST 6.0
Skin Prick Test 7.8
Pulmonary Function Test (PFT) 18.6
Components of medical surveillance
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
TrackingSuccessofPrevention
•Prevalence: percent of workers with LAA at a point in time• Incidence: percent of new cases of LAA (among those without LAA) over a period of time
Knowledge of LAA prevalence and incidence by size of workforce
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Knowledge of LAA prevalence and incidence by type of organization
PrevalenceandIncidenceofLAAamongorganizationsreportingrates
Figure 5. Reported Prevalence and Incidence of LAAStave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Workers with LAA (non‐asthma): Percent
Are excluded from all work with animals
0
Are excluded from work with the animal species that they are allergic to
5.9
May be excluded or restricted depending on severity of allergy
55.1
Can continue to work with animals with restrictions
33.2
Can continue to work with animals without restrictions
5.9
Work restriction policies for workers with LAA
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Workers with laboratory animal asthma:
Percent
Are excluded from all work with animals 10.3Are excluded from work with the animal species that they are allergic to
12.4
May be excluded or restricted depending on severity of asthma
61.6
Can continue to work with animals with restrictions
20.0
Can continue to work with animals without restrictions
5.4
Work restriction policies for workers with laboratory animal asthma
Stave GM, Darcey DJ. Prevention of Laboratory Animal Allergy in the United States: A National Survey. J Occup Environ Med. 2012 May;34(5):558‐563.
Conclusions Laboratory animal allergy is a common, but preventable occupational illness A comprehensive LAA prevention program can virtually eliminate the development of first or primary LAA However, if someone has developed LAA, they remain at risk for developing allergy to additional species and this is more difficult to prevent
Conclusions In a national survey, there is broad variation in policy and practice Only 25% of respondents knew the prevalence and incidence rates for LAA There is a need for more organizations with successful LAA prevention programs to publish their experience It would be helpful to have a consensus process to ensure greater protection of workers
Thanks! Leslie Elliott, Lisa Pompeii, Robin Fisher, Bill Saunders, and Steven Murray for their work on analysis of the Glaxo and Glaxo Wellcome LAA prevention programs The Occupational Health staff from Burroughs Wellcome, Glaxo, Glaxo Wellcome, and GlaxoSmithKline The employees and management from Burroughs Wellcome, Glaxo, Glaxo Wellcome, and GlaxoSmithKline who work with laboratory animals and who supported, participated in, and worked to improve the LAA prevention program Fuzz Harrison and Dr. Robert Bush for their collaboration. Dr. Dennis Darcey and Rosemary Thorne for their collaboration on the national survey of LAA prevention practices
ReferenceforMedicalSurveillanceQuestionnaire• Bush RK, Stave GM. Laboratory Animal Allergy: An Update. ILAR Journal 2003; 44(1):28‐51 Appendices C,D.
Thankyou!Gregg M. [email protected]