Progress with Structure-Activity Relationship modelling of occupational chemical respiratory sensitizers.
OBJECTIVE
This appraises currently available computer-based ('in silico') models relating the molecular structure of low molecular weight compounds to their respiratory sensitization hazard. The present review places focus on the two main applications of such structure--activity relationship (SAR) models: hypotheses on disease mechanisms and toxicological prediction.


RESULTS
Analyses of the chemical structures of low molecular weight organic compounds known to have caused occupational asthma has led to the development of mechanistic alerts usually based on electrophilic reaction chemistry and protein cross-linking potential. Protein cross-linking potential has also been found to be a consistent feature of chemicals that have caused human cases of hypersensitivity pneumonitis. Stepwise iteration of quantitative SAR (QSAR) modelling has shown appreciable improvements in predictivity for occupational asthma hazard and useful prospects for practical application. A good case has also been made for the potential use of structural alert-based mechanistic SARs in predictive toxicology.


CONCLUSIONS
Further understanding of the molecular interactions between chemical respiratory sensitizers and components of human proteins have been obtained from in-vitro and in-silico techniques. There have been developments in both qualitative (mechanistic) SARs and QSARs, which offer potential for use in a predictive algorithm for the toxicological screening of industrial chemicals for respiratory sensitization potential.
Centre for Occupational and Environmental Health, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
Martin J
MJ
Seed
Raymond M
RM
Agius
D000395:Air Pollutants, Occupational / Q000009:adverse effects / Q000276:immunology*; D000485:Allergens / Q000276:immunology*; D000542:Alveolitis, Extrinsic Allergic / Q000175:diagnosis*; D000818:Animals; D059366:Asthma, Occupational / Q000175:diagnosis*; D003198:Computer Simulation; D006801:Humans; D008403:Mass Screening; D009930:Organic Chemicals / Q000276:immunology*; D011379:Prognosis; D021281:Quantitative Structure-Activity Relationship; D012306:Risk
D000395:Air Pollutants, Occupational; D000485:Allergens; D009930:Organic Chemicals