Thursday, 05 October 2017 18:07

Respiratory Sensitivity: Researchers Recommend Testing Strategy using Cell and Computer Methods Featured

Respiratory allergens causing diseases like asthma can be identified using methods based on human cells and computer programs. convinced of this, an international research team has developed an investigative approach that was presented in the journal Applied In Vitro Toxicology.

Only around 80 chemicals are currently known as respiratory allergens, but there are likely to be more. Exposure is mainly in the occupational field. However, there is still no standardized or regulatory-accepted test methods approved for detecting chemicals that act as strong and irreversible respiratory allergens. In addition, the immune systems as well as the respiratory systems of humans, rats and mice differ considerably, so that an assessment of allergens based on animal experiments would be questionable. Apart from that, the reaction to an allergen within a human population can be variable.

In an workshop, the research team consisting of by Dr. Janine Ezendam (Dutch National Institute for Public Health and the Environment (RIVM)), Kristie Sullivan (Physicians Committee for Responsible Medicine (PCRM)), Dr. Steven Enoch (School of Pharmacy and Biomolecular Sciences of Liverpool John Moores University), Dr. Katharina Sewald (Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM)), Dr. Erwin Roggen (founder and director of 3R Management & Consulting ApS) and Dr. Stella Cochrane (Unilever SEAC) has collected and analysed available data from svientific literature on chemicals with low molecular weight. With the resulte the scientists have created a so-called adverse outcome pathway (AOP). They were inspired by an already existing integrated test strategy for skin sensitization, which modification even allows a determination of the strength of skin allergens.

An AOP is a collection of existing data on how the exposure of a given chemical causes a sequence of biological changes in the body, which ultimately leads to illness or injury to the body (human, animal or population).

It consists essentially of three parts:
- the molecular initiating event (MIE) after the body has been exposed to the chemical,
- the key events and key event relationships, i. e. the process in the cells following the MIE that leads to cell damage or alteration in the organ function,
- the actual damaging result (adverse outcome), e. g. a disease.

With regard to the respiratory sensitization:
- the MIE would be the covalent binding of a protein to an organic chemical of low molecular weight (hapten). Together, the two form a hapten-carrier complex.
- Possible key events would be, for example, a T-helper cell-mediated triggering of immunoglobulins (antibodies) and inflammatory processes caused by eosinophils, as described in the researchers` publication.
- The adverse outcome could be, for instance, asthma or a pulmonary fibrosis.

However, the researchers are not yet aware of the immune system's defensive mechanisms. Here and elsewhere there are still gaps in knowledge, which can now be investigated and supplemented with computer programs and cell tests.

In addition, it is now believed that asthma is an umbrella disease with multiple heterogeneous phenotypes.

The aim of the AOP is to identify information gaps and research needs as well as to highlight the need for further development of human-specific methods in form of an integrated testing strategy, consisting of a sequence of in silico, in chemico, in vitro and - only as a last resort - in vivo methods, in order to reliably detect particularly work-related respiratory allergens.

Original publication:
Sullivan Kristie M., Enoch Steven J., Ezendam Janine, Sewald Katherina, Rye Erwin L. & Cochrane Stella (2017): An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility of In Vitro and In Silico Methods in a Regulatory Context. Applied In Vitro Toxicology. September 2017,3 (3): 213-226.

Sources:
http://www.pcrm.org/media/news/toxicologists-recommend-human-cell-based-methods-to-identify-asthma-causing-chemicals
https://chemicalwatch.com/crmhub/59138/respiratory-sensitisation-key-events-outlined-in-aop?pa=true