Laboratory Animal Allergies CareGroup Occupational Health Network Occupational Medicine Grand Rounds November 9, 2000

Reid Boswell, M.D., M.P.H. Medical Director Mount Auburn Hospital Occupational Health Services

Lab Animal Allergies (LAA) §Definitions §Clinical Manifestations §Epidemiology §Specific Allergens §Diagnosis §Risk Factors §Prevention §Summary §References

Allergy § Hypersensitivity reaction resulting from specific interactions between antigens (allergens) and either antibodies or sensitized lymphocytes.

Gel and Coombs Classification of Hypersensitivity Reactions §Type 1: Immediate, IgE mediated. Results in release of inflammatory mediators (histamine, leukotrienes, etc.). Examples include urticaria, anaphylaxis §Type 2: Cytotoxic. Antigen-antibody complex results in activation of cytotoxic cells. Examples: transfusion reactions, Goodpasture’s syndrome.

Gel and Coombs, continued §Type 3: Immune complex reactions resulting in deposition of soluble complexes in tissue. Examples: vasculitis, serum sickness (drug reactions), SLE §Type 4: Delayed, cell-mediated caused by sensitized lymphocytes. Examples: tuberculin reaction, RA, sarcoidosis, Wegener’s granulomatosis.

Clinical Manifestations § Rhinoconjunctivitis: l Sneezing l Nasal congestion l Itchy, watery eyes l Occurs in up to 80% of symptomatic workers.

Clinical Manifestations §Dermatologic: l Usually contact urticaria (hives) l Itchy, red papules (maculopapular eruption) l Occurs in up to 40% of symptomatic workers.

Clinical Manifestations §Asthma: Wheezing, chest tightness, and cough caused by spasm of small airways. Occurs in 20-30% of symptomatic workers. §Asthma is the most serious symptom and may not be reversible after removal from exposure.

Clinical Manifestations §Most workers have a combination of symptoms. §Symptoms often progress from mild rhinitis to severe asthma with continued exposure.

§Prevalence (or “point prevalence”):The number of existing cases of a given disease at a given point in time divided by the total number of people in the exposed population. §Incidence (or “cumulative incidence”): The number of new cases of a disease during a given period (usually a year) divided by the total at risk population. Epidemiology 101

The PREVALENCE of lab animal allergies ranges from 11-44%, depending on the study. §Prevalence estimates vary primarily because of differing ways of defining the disease: l Objective tests vs. subjective symptom reporting. l The lowest estimates were from studies which relied on employer reports; the highest estimates simply use self-reporting of symptoms (i.e. “do you ever get a stuffy nose at work”).

Aoyama, et al, British Journal of Industrial Medicine, 1992 §Probably the largest cross sectional study involving lab animal allergies: l 26% of workers exposed to mice l 25% of workers exposed to rats l 31% of workers exposed to guinea pigs l 30% of workers exposed to rabbits l 26% of workers exposed to hamsters l 25% of workers exposed to dogs l 30% of workers exposed to cats l 24% of workers exposed to monkeys

Hunskaar, 1993 §Meta-analysis of 19 different studies on lab animal allergies showed a pooled average prevalence of 20.9%.

Prevalence of Asthma §Aoyama found a 9% prevalence of asthma symptoms among exposed workers §Others found a prevalence of 4-22%. §None of these studies differentiated between those who developed asthma as a result of their animal exposure versus pre-existing asthma.

INCIDENCE of LAA §Determining the incidence of new cases is more difficult to study §One study found a one year incidence of 15% with a 2% incidence of asthma §Another study examined cohorts of new workers each year for several years and found the highest incidence to be 37% with a steady decrease over several years to 10%.

Onset of Symptoms §Cullinan, et al,, 1994: Prospective study of new workers with no previous rat exposure: l Range of days from time of employment to onset of symptoms l Mean duration of employment before symptom onset was 365 days for chest symptoms 214 days for nose and eye symptoms 335 days for skin symptoms

Onset of Symptoms, continued §In general, most who develop allergies will do so within 3 years of employment §One third are symptomatic in the first year, 70% within 3 years. §About 70% of those who eventually develop asthma will do so within 3 years of developing initial allergy symptoms.

Specific Animal Allergens §Urine is the major source of rodent allergen exposure. §Mouse: l Mus m 1 (prealbumin): Previously known as major urinary protein. Found primarily in urine, but also in dander and hair l Mus m 2: Found mostly in hair and dander l Albumin: Found in serum

Animal Allergens, continued §Rats: l Rat n 1A/Rat n 1B (alpha-2 globulin): Found in urine, hair, and dander. l Albumin: serum

Animal Allergens, continued §Guinea Pig: Cav p 1 and Cav p 2, found in hair, dander, and urine. §Rabbit: Ory c 1 in hair, dander, and saliva; and Ory c 2, found in hair, dander, and urine. §Cat: Fel d 1 in hair, dander, and saliva; and albumin in serum. §Dog: Can f 1 in hair, dander, and saliva; and albumin in serum.

Environmental Distribution of Lab Animal Allergens §Mouse allergens are on particles ranging from microns. §Rat allergens are on particles ranging from <1-20 microns (average 7 microns). §Most particles are respirable and can remain airborne for hours.

Allergen Concentrations by Task Eggleston, et al, 1989 §Cleaning/ Feeding: 9-70 ng/cubic meter: §Handling/Injecting: 0-48 ng/cubic meter §Surgery/Sacrifice:0-15 ng/cubic meter

Diagnosis §Temporal relationship of the development of symptoms to work with lab animals §Across shift changes in FEV1 or PEF while working with lab animals. §Skin testing to specific animal proteins (SPT). §Radioallergosorbent tests (RAST): Measures the amount of IgE specific to a particular protein.

Risk Factors for the Development of Lab Animal Allergies §History of Atopy: Genetic predisposition to allergic conditions. §History of cat or dog allergy §Job title/job tasks §Positive skin tests and/or RAST test. §Elevated total IgE levels

Atopy (history of pre-existing seasonal allergies and a positive response to skin testing of common environmental allergens)

Skin Tests (meta-analysis by Bush, et al, 1998)

RAST (radioallergosorbent test)

Limitations of RAST and Skin Testing §Allergens are not standardized. §The specific allergens are not available or standardized (only extracts of animal urine or pelts) §Technique may not be standardized.

Using a History of Atopy as a Pre-screening tool §36% of the population has a history of atopy §About a third of those with atopy will develop lab animal allergies. §Therefore, eliminating applicants with a history of atopy would result in eliminating 2/3 of applicants who would not go on to develop LAA.

History of Dog or Cat Allergy (Hollander, et al, 1996)

Total IgE Levels (Hollander, et al, 1996)

Children of Workers Exposed to Lab Animals: Positive Skin Tests (Krakowiak, et al, 1999)

Preventive Strategies §Engineering Controls: l HEPA ventilated cage racks and filter top cages l Direct airflow away from workers and toward back of cages (consider laminar flow ventilation) l Increase humidity in animal areas (40-50% rh) l Use of low dust bedding and less allergenic animals l Increase ventilation and install HEPA system

Preventive Strategies §Administrative Controls: l Perform animal manipulations in ventilated hoods. l Education and training to workers l Decreased animal density l Medical surveillance programs l Job assignment for at risk workers (?)

Preventive Strategies §Personal Protective Equipment l Lab coats l Gloves l Safety glasses or goggles l Masks, preferably fit-tested HEPA respirators l Restriction of street clothing

Medical Surveillance §Baseline and periodic physical exams §Periodic allergy questionnaires (q 6 months) §Baseline and periodic pre and post shift spirometry or serial peak flow determinations §?? Baseline and periodic SPT or RAST

Summary §The prevalence of LAA is about 25-30%, with about 10% prevalence of asthma. §While initial symptoms can be mild, they can progress to permanently disabling asthma fairly quickly. §Those who will develop LAA will usually become symptomatic within 3 years of first exposure. §Many workers who develop symptoms will not report them and simply leave their job.

Summary §The most common sources of allergens in the lab are rat and mouse urinary proteins. §Diagnosis of LAA can be difficult, especially establishing work relatedness. §Common diagnostic tests (RAST and SPT) have limitations. §Risk factors include: history of atopy, +SPT or RAST, allergy to cats or dogs, elevated total IgE.

Summary §Risk factors do not include gender or history of smoking. §Denying employment to applicants with risk factors is impractical and probably illegal. §Preventive strategies include engineering controls, administrative controls, and personal protective equipment. §Medical surveillance should include baseline and periodic PFT’s (preferably pre and post shift) and exams, as well as periodic questionnaires.

References §Bush, et al, “Laboratory animal allergy”, J Allergy Clin Immunol 1998; 102: §Seward, “Occupational Allergy to Animals” Occupational Medicine State of the Art Reviews, 1999; 14(2): §Krakowiak, et al, “Allergy to laboratory animals in children of parents occupationally exposed to mice, rats, and hamsters”, Eur Resp J, 1999;14:

References §Hollander,et al, “Cat and dog allergy and total IgE as risk factors of laboratory animal allergy”, J Allergy Clin Immunol, 1996;98(3): §Heederik, et al, “Exposure-response relationships for work-related sensitization in workers exposed to rat urinary allergens: Results from a pooled study”, J Allergy Clin Immunol, 1999; 103:

References §Fisher, et al, “Prevention of laboratory animal allergy”, J Occup Environ Med, 1998; 40(7): §NIOSH ALERT “Preventing Asthma in Animal Handlers” DHHS (NIOSH) Publication No , January, 1998.: Available on the NIOSH web site: cdc.gov/niosh