Moving Toward a Broader Definition

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 hypersensitivity—not 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 sensitizer—if 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 evaluation.

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 asthma).

• 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.

CONTROL MEASURES

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 operation.
• 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 asthmagens.
• 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.

Evaluation of Respiratory Sensitizer Case Studies

Important Factors to Consider

There must be evidence that a substance can cause respiratory sensitization (normally derived from human experience).*

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.