Moving Toward a Broader
One of the more difficult and
controversial areas of regulatory toxicology in recent years has been the definition
of substance-related asthma. The mechanisms by which a variety of occupational
agents may evoke asthma are largely unknown. There has been much debate over
the distinction between occupational asthma caused by an immune response and
that caused by exposure to a highly irritating agent. The latter condition is
sometimes called Reactive Airways Dysfunction or RADS.
As explained in a publication
from the UK Health and Safety Executive, this distinction is unclear because
of a lack of understanding of the underlying toxicological mechanisms, confused
terminology, the absence of internationally accepted experimental tests, inconclusive
clinical data, and doubt concerning how different exposure patterns and routes
impact the risk of occupational asthma.*
Occupational asthma is one
of the most important occupational respiratory illnesses in terms of the degree
of disability it causes and the total number of cases. Regardless of whether
it results from an immune response or an irritant reaction to a substance, the
symptoms are virtually the same: airway hypersensitivity characterized by episodes
of cough, wheezing, chest tightness and breathlessness. Occupational asthma
can result in severe and potentially fatal breathing problems.
Today we are seeing a movement
toward focusing less on categorizing asthma as immune or irritant, and more
on classifying any chemical that can produce such a reaction as a respiratory
sensitizer. This represents a significant change in thinking, since the
term respiratory sensitizer has traditionally been interpreted to imply an underlying
immunological mechanism for the production of asthma.
In Europe, regulators have
accepted a broader definition for this hazard classification. The European Union
(EU) defines respiratory sensitizer as a substance that causes occupational
asthma. The EU identifies individual, well-substantiated cases of such substances
having caused asthma and considers the prevalence of such instances, relative
to the number of people exposed. The EU criteria makes it clear that, to be
classified as a respiratory sensitizer, a substance must induce or initiate
the state of airways hypersensitivitynot provoke an existing condition.
Due to the uncertainty and
inconclusive evidence about the mechanism(s) involved in the development of
asthma, the EU focuses on evidence that a substance has the ability to cause
asthma, rather than on the existence of a specific underlying mechanism.
The proposed criteria for the
Global Harmonized System (GHS) of hazardous substances classification acknowledge
that the mechanisms by which substances induce symptoms of asthma are not yet
fully known, and that immunological mechanisms do not have to be demon-strated.
In Canada, the Controlled Products
Regulations (CPR) define a pure substance or tested mixture as a respiratory
tract sensitizerif there is evidence that shows that it causes respiratory
tract sensitization in persons following exposure to it in the work place.
(CPR Section 56) Respiratory tract sensitization is defined as the development
in a person who is not atopic of severe asthma-like symptoms on exposure to
a substance to which the person has been exposed. (CPR Section 32) Cases
involving atopic persons (those with a history of allergies) are excluded from
According to Health Canada,
there is no requirement that immunological mechanisms have to be demonstrated.
Asthma-like symptoms could be caused by an immune response to the chemical,
an irritant response, some combination of these two, or mechanisms as yet not
defined. Two valid case reports would be accepted as sufficient evidence.
The term respiratory sensitizer
is taking on a new definition: substance with the potential to act, through
whatever mechanism, to create a situation of airway hypersensitivity where none
previously existed. Meanwhile an alternate term has been coined which removes
any connotation to an immune basis. The new term is asthmagen (agent which causes
- Taken from a publication
from the UK Health and Safety Executive, Asthmagen?Critical Assessments
of the Evidence for Agents Implicated in Occupational Asthma, ISBN 0 7176
1465 4. Copies available from P.O. Box 1999, Sudbury, Suffolk, CO10 6FS, Tel.
01787-881165 or fax 01787-3133995. Anyone who buys a copy of this publication
will be entitled to a free update of the material published until 1999.
for reducing or eliminating
occurrences of occupational asthma
- Substitute asthmagens with
less hazardous materials.
- Limit exposure at the source.
Contain, enclose or isolate the substance (closed handling system preferred).
- Use effective local exhaust
ventilation and other engineering controls.
- Consider personal protective
equipment as a last resort or for special situations, e.g. a spill clean-up
- Administrative controls:
- Educate staff on hazards
and early signs and symptoms.
- Use medical surveillance
programs to identify at-risk individuals and detect symptoms early.
- Make sure no one works alone.
Alternatively, conduct routine visual checks or have a telephone call-in procedure
in place for the continued safety of lone workers or workers in remote locations.
- Inform maintenance and emergency
personnel of hazards.
- Unprotected persons should
avoid all contact with materials classified as respiratory sensitizers or
- Once sensitization has occurred,
the best option is complete removal from the work environment. Deaths have
occurred when sensitized persons continued to work in an environment where
they were exposed to very small amounts of asthmagens.
Respiratory Sensitizer Case Studies
Important Factors to
There must be evidence that
a substance can cause respiratory sensitization (normally derived from human
The agent in question must
be specifically identified (e.g. no confusion regarding chemical identity).
A relationship between exposure
to the chemical and development of respiratory sensitivity must be demonstrated.
Asthmatic symptoms would include
cough, wheezing, shortness of breath, constriction of the airways.
Other potential causes of the
reaction must be excluded, such as a history of allergies (personal and family)and/or
a previously identified history of asthma, including childhood asthma.
Smoking history is considered
a possible contributing or causal factor.
Lung function tests show significant
reversible or variable airflow obstruction and/or non-specific bronchial hyperresponsiveness.
Results from bronchial provocation
tests (with the agent to which the person is exposed at work) are positive.
The agent is related to chemical
families known to produce occupational asthma e.g. isocyanates, acid anhydrides.
NOTE: Many case reports do
not contain enough information for regulatory evaluation. Therefore, one must
often take a balanced view of all of the information available and make the
best scientific judgement possible.
* At present, recognized, validated
animal models for respiratory sensitization are not available.