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: Sneezing Nasal congestion Itchy, watery eyes Occurs in up to 80% of symptomatic workers.

Clinical Manifestations

Dermatologic: Usually contact urticaria (hives) Itchy, red papules (maculopapular eruption) 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: Objective tests vs. subjective symptom

reporting. 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:

26% of workers exposed to mice 25% of workers exposed to rats 31% of workers exposed to guinea pigs 30% of workers exposed to rabbits 26% of workers exposed to hamsters 25% of workers exposed to dogs 30% of workers exposed to cats 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: Range of 30-1369 days from time of

employment to onset of symptoms 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: Mus m 1 (prealbumin): Previously known as

major urinary protein. Found primarily in urine, but also in dander and hair

Mus m 2: Found mostly in hair and dander Albumin: Found in serum

Animal Allergens, continued

Rats: Rat n 1A/Rat n 1B (alpha-2 globulin): Found in

urine, hair, and dander. Albumin: serum

Animal Allergens, continuedGuinea 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 3.3-18 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 TaskEggleston, et al, 1989

Cleaning/ Feeding: 9-70 ng/cubic meter:

Handling/Injecting: 0-48 ng/cubic meter

Surgery/Sacrifice: 0-15 ng/cubic meter

DiagnosisTemporal relationship of the development of

symptoms to work with lab animalsAcross 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 allergyJob title/job tasksPositive 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)

Atopy Symptoms Positive skin test (to animal allergen)

Yes(36% )

36% 32%

No(64%)

15% 6%

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

Skin test + - - +

Symptoms + - + -

10%(n=94)

71%(n=696)

6%(n=57)

13%(n=124)

RAST(radioallergosorbent test)

RAST + - - +

Symptoms + - + -

5%(n=23)

88%(n=384)

5%(n=22)

2%(n=8)

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)

RAT MOUSE

Negative skin tests tocommon allergens

5.4% 0.9%

Positivegrass/mite/tree

Negative dog/cat

6.0% 1.4%

Positive dog/cat fur 34.8% 13.3%

Total IgE Levels(Hollander, et al, 1996)

RAT MOUSE

Total IgE<100 kU/L

7.7% 2.6%

Total IgE>100 kU/L

33.3% 10.0%

Allergy symptoms to pets +SPT to cat or dog Total IgE >100 kU/L

RAT MOUSE

None present 1.8% 0.43%

One present 21% 6.3%

Two present 46% 17.4%

Children of Workers Exposed to Lab Animals: Positive Skin Tests

(Krakowiak, et al, 1999)

0

2

4

6

8

10

12

14

Mouse Rat Hamster

With ExposureWithout Exposure

Preventive StrategiesEngineering Controls:

HEPA ventilated cage racks and filter top cages Direct airflow away from workers and toward

back of cages (consider laminar flow ventilation)

Increase humidity in animal areas (40-50% rh) Use of low dust bedding and less allergenic

animals Increase ventilation and install HEPA system

Preventive Strategies

Administrative Controls: Perform animal manipulations in ventilated

hoods. Education and training to workers Decreased animal density Medical surveillance programs Job assignment for at risk workers (?)

Preventive Strategies

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

Medical Surveillance

Baseline and periodic physical examsPeriodic allergy questionnaires (q 6 months)Baseline and periodic pre and post shift

spirometry or serial peak flow determinations

?? Baseline and periodic SPT or RAST

SummaryThe 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.

SummaryThe 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.

SummaryRisk 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: 99-112.

Seward, “Occupational Allergy to Animals” Occupational Medicine State of the Art Reviews, 1999; 14(2): 285-303

Krakowiak, et al, “Allergy to laboratory animals in children of parents occupationally exposed to mice, rats, and hamsters”, Eur Resp J, 1999;14:352-356.

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):545-554.

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; 103:678-684.

ReferencesFisher, et al, “Prevention of laboratory

animal allergy”, J Occup Environ Med, 1998; 40(7):609-613.

NIOSH ALERT “Preventing Asthma in Animal Handlers” DHHS (NIOSH) Publication No. 97-116, January, 1998.: Available on the NIOSH web site: cdc.gov/niosh