Thresholds in chemical respiratory sensitisation

Abstract

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.

Activation of T cells by dendritic cells exposed to a reference sensitizer: Towards a promising model to assess the allergenic potential of chemicals

“…16919‐58‐7), a reference sensitizer . TC activation was evaluated by measuring cell proliferation, the expression of membrane markers, and cytokine secretion . To develop this model, the optimal conditions for cell culture were first determined.…”

“…Occupational allergies constitute an important health issue that may be caused, in particular, by low molecular weight chemicals . Exposure to these chemicals mainly induces contact hypersensitivity and respiratory sensitization, both of which can have important adverse health effects and can lead to detrimental socioeconomic consequences . Two pieces of legislation—(1) the 2008 amendment to the Regulation under the United Nations Globally Harmonized System for Classification, Labeling, and Packaging of substances and mixtures (Regulation [EC] No.…”

Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches

“…However, a portion of the population is already sensitized and it would be theoretically more health protective to prevent the elicitation of allergic responses in these individuals. Endpoints under consideration as the basis of risk assessment efforts and potentially capable of identifying persons who are in the process of being sensitized include: 1) lymphocyte proliferative responses, 2) changes in cytokine expression, 3) IgE antibodies, and 4) chemical challenges (e.g., patch test) (Cochrane et al, 2015). Because the biological response is complex (sensitization vs elicitation) and potency is difficult to estimate in a dose-response context, setting quantitative OELs has been limited primarily to chemicals with significant epidemiological data.…”

Testing Human Skin and Respiratory Sensitizers—What Is Good Enough?

“…Consequently, the availability of today’s high-throughput testing approaches [24], originally developed by the pharmaceutical industry [6], have the potential to pave the way for the next generation’s stand alone tests for assessing the risk for skin sensitization. A prediction of which allergens will induce respiratory sensitization, remains a significant challenge, because our understanding of the underlying biological properties is incomplete [25,26]. Of note, a genomic biomarker signature for the classification of respiratory sensitizers was, however, recently identified [27].…”