Development of Mechanism-Based Structural Alerts for Respiratory Sensitization Hazard Identification

Enoch, Steven J.; Seed, Martin; Roberts, David W.; Cronin, Mark T.D.; Stocks, Susan Jill; Agius, Raymond

doi:10.1021/tx3003092

Cited by 64 publications

(72 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To acquire immunogenic potential they must form stable associations with protein (hapten-protein conjugates). Mechanistic chemistry studies have revealed that chemical respiratory allergens can be assigned to one of six electrophilic mechanistic domains, with harder (stronger) electrophilic mechanisms such as acylation being more prevalent than softer (weaker) mechanisms, with the hypothesis being that the harder nucleophile lysine is the favoured biological nucleophile for sensitisation of the respiratory tract (Enoch et al, 2012). Details of the mechanisms involved are, however, still poorly understood, though the possible importance of lysine reactivity in sensitisation of the respiratory tract by chemical allergens is supported by some in chemico and in vitro studies (Hopkins et al, 2005;Lalko et al, 2011Lalko et al, , 2012Lalko et al, , 2013b.…”

Section: Mechanisms Through Which Sensitisation Of the Respiratory Trmentioning

confidence: 99%

“…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: 99%

See 1 more Smart Citation

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

Section: Mechanisms Through Which Sensitisation Of the Respiratory Trmentioning

confidence: 99%

Section: Quantitative Structure Activity Relationships (Qsar)mentioning

confidence: 99%

Thresholds in chemical respiratory sensitisation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…was "classified incorrectly" and considered sensitizing effects on the airways to be plausible based on a detailed review of the possible reactions of azodicarbonamide. They suggested that the mechanism responsible for protein reactivity was a Michael addition to the N=N double bond activated by the carbonyl groups (Enoch et al 2010(Enoch et al , 2011(Enoch et al , 2012. The above-mentioned earlier study on the reaction of azodicarbonamide with SH groups in proteins of dough (Tsen 1963; see Section "Mechanism of Action") and a study on the antiviral effect of substituted azodicarbonamides (Hill and Vederas 1999; see Section "Mechanism of Action") are referred by the authors as evidence for the postulated protein binding.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

Azodicarbonamide [MAK Value Documentation, 2017]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

View full text Add to dashboard Cite

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated azodicarbonamide [123‐77‐3] to derive a maximum concentration at the workplace (MAK value), considering all toxicological endpoints. Available publications and unpublished study reports are described in detail. The critical effect is the occurrence of reactions in the airways in exposed workers. In the view of the Commission, the present inhalation studies in animals are not appropriate for the derivation of a MAK value as human airways are probably more sensitive than rodent airways. The workplace investigations show no clear correlation of exposure and frequency of respiratory symptoms. Nevertheless, from the NOAEC of 36 µg/m 3 for lung function measurements in a small group of injection‐molding workers in the plastics industry, a MAK value of 20 µg/m 3 I is established. Due to the incomplete information on the relevant exposure scenario and the uncertainty regarding first occurrence of workplace related symptoms, this value should be considered as preliminary. As local effects are critical, azodicarbonamide is assigned to Peak Limitation Category I and the default excursion factor of 1 is designated. Since developmental toxicity studies are not available, Pregnancy Risk Group D is assigned. There are no carcinogenicity studies and azodicarbonamide is not regarded as germ cell mutagen. Skin contact is not expected to contribute significantly to systemic toxicity. The metabolism of azodicarbonamide and its reactivity do not point to stable protein binding in vivo and therefore, skin or respiratory sensitization is unlikely. Clear‐cut clinical findings or positive results from animal studies on skin sensitization are not available, but the negative results in experimental animals are difficult to evaluate due to the low solubility of the compound. Although azodicarbonamide affects the respiratory tract in several case reports with positive bronchial provocation tests, sensitization by a known mechanism is not adequately verified. Additionally, it appears questionable whether a mono‐causal relationship of respiratory symptoms and azodicarbonamide exposure can really be assumed. In conclusion, a sensitizing effect of azodicarbonamide is not sufficiently proven. Completed: March 22, 2017

show abstract

“…Consider the 398 two chemicals ethyl cyanoacrylate and methyl tiglate which can both react via Michael addition to form a 399 covalent bond with a protein (Figure 1). Ethyl cyanoacrylate is a potent respiratory sensitiser, whilst there 400 have been no reports of methyl tiglate causing respiratory sensitization in humans (Enoch et al, 2012). 401…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…This mechanistic rationale is a significant improvement on the previous hypothesis that 404 all chemicals that cause respiratory sensitization must have multiple reactive centers (Agius et al, 1991), 405 and by the same token may explain how relatively weak electrophiles may cause sensitisation if they are 406 also capable of protein cross-linking (for example di-carbonyl conatining chemicals acting via a Schiff 407 base mechanism).). 408 The availability of the larger data set of respiratory sensitization data enabled further analysis into the 413 detailed mechanistic chemistry associated with the MIE for LMW chemicals (Enoch et al, 2012), resulting 414 in the identification and publication of a set of structural alerts that defined the chemistry associated with 415 covalent protein binding in the lung. An important aspect is the analysis of the associated metadata for 416 each structural alert, which documents the reaction mechanism and supporting peer-reviewed literature.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%