Methods for the prediction of low-molecular-weight occupational respiratory sensitizers

Seed, Martin; Cullinan, Paul; Agius, Raymond

doi:10.1097/aci.0b013e3282f4cadd

Cited by 42 publications

(29 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, an understanding of structure-activity relationships may provide insight into the molecular mechanisms involved in the initial chemical reaction between environmental chemicals and the human host. 10 For some reactive groups, like carbonyl and amine, the presence of 2 or more fragments is associated with more significant odds ratios, supporting the hypothesis that bifunctional or polyfunctional chemicals-that is, those with cross-linking potential-are more likely to be asthmagens. Similarly, multiple chlorine atoms are required to confer allergenicity of hexachloroplatinate salts.…”

Section: Role Of Exposure In Pathophysiologic Mechanisms Characteristmentioning

confidence: 84%

“…Because of the uncertainties regarding the molecular mechanism for LMW respiratory sensitizers, quantitative structure-activity relationships seem particularly appropriate because they make no a priori mechanistic assumptions. 9,10 Using a large data set of respiratory sensitizers and inactive controls, Cunningham et al 11 identified biophores and developed a categorical structure-activity model whose predictive power gave a sensitivity of 89% and a specificity of 95%. Jarvis et al 9 demonstrated that the odds ratios that indicate a chemical substructure is present in an asthmagenic compound compared with a control are elevated for a range of fragments, including reactive groups such as isocyanate, anhydride, acrylate, nitrogen, carbonyl, or amine.…”

Section: Role Of Exposure In Pathophysiologic Mechanisms Characteristmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of occupational asthma

Maestrelli

Boschetto

Fabbri

et al. 2009

Journal of Allergy and Clinical Immunology

189

148

View full text Add to dashboard Cite

Section: Role Of Exposure In Pathophysiologic Mechanisms Characteristmentioning

confidence: 84%

Section: Role Of Exposure In Pathophysiologic Mechanisms Characteristmentioning

confidence: 99%

Mechanisms of occupational asthma

Maestrelli

Boschetto

Fabbri

et al. 2009

Journal of Allergy and Clinical Immunology

189

148

View full text Add to dashboard Cite

“…More recently there has been a growing commitment to examining the chemical characteristics of respiratory allergens. Progress is being made, particularly with respect to electrophilic reaction chemistry (Seed et al, 2008;Seed and Agius, 2010;Enoch et al, 2009Enoch et al, , 2010Enoch et al, , 2012Dik et al, 2014). However, despite some achievements the models available currently are not validated for the purposes of hazard identification, and are not suited to consideration of dose-response relationships during the acquisition of sensitisation, or the definition of threshold values.…”

Section: Quantitative Structure Activity Relationships (Qsar)mentioning

confidence: 97%

Thresholds in chemical respiratory sensitisation

et al. 2015

View full text Add to dashboard Cite

There is a continuing interest in determining whether it is possible to identify thresholds for chemical allergy. Here allergic sensitisation of the respiratory tract by chemicals is considered in this context. This is an important occupational health problem, being associated with rhinitis and asthma, and in addition provides toxicologists and risk assessors with a number of challenges. In common with all forms of allergic disease chemical respiratory allergy develops in two phases. In the first (induction) phase exposure to a chemical allergen (by an appropriate route of exposure) causes immunological priming and sensitisation of the respiratory tract. The second (elicitation) phase is triggered if a sensitised subject is exposed subsequently to the same chemical allergen via inhalation. A secondary immune response will be provoked in the respiratory tract resulting in inflammation and the signs and symptoms of a respiratory hypersensitivity reaction. In this article attention has focused on the identification of threshold values during the acquisition of sensitisation. Current mechanistic understanding of allergy is such that it can be assumed that the development of sensitisation (and also the elicitation of an allergic reaction) is a threshold phenomenon; there will be levels of exposure below which sensitisation will not be acquired. That is, all immune responses, including allergic sensitisation, have threshold requirement for the availability of antigen/allergen, below which a response will fail to develop. The issue addressed here is whether there are methods available or clinical/epidemiological data that permit the identification of such thresholds. This document reviews briefly relevant human studies of occupational asthma, and experimental models that have been developed (or are being developed) for the identification and characterisation of chemical respiratory allergens. The main conclusion drawn is that although there is evidence that the acquisition of sensitisation to chemical respiratory allergens is a dose-related phenomenon, and that thresholds exist, it is frequently difficult to define accurate numerical values for threshold exposure levels. Nevertheless, based on occupational exposure data it may sometimes be possible to derive levels of exposure in the workplace, which are safe. An additional observation is the lack currently of suitable experimental methods for both routine hazard characterisation and the measurement of thresholds, and that such methods are still some way off. Given the current trajectory of toxicology, and the move towards the use of non-animal in vitro and/or in silico) methods, there is a need to consider the development of alternative approaches for the identification and characterisation of respiratory sensitisation hazards, and for risk assessment.

show abstract

“…New tests should be based on mechanistic understanding and should be preferentially restricted to in vitro assays. Various methods have been used to develop (Q)SARs models for prediction of low-molecular-weight organic chemical respiratory sensitizers (Seed et al, 2008). Such methods, however, still require further corroboration from animal or human data.…”

Section: In Vitro Assessment Of Respiratory Sensitizersmentioning

confidence: 99%