title: 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.
authors.affiliation: Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire, Mk44 1LQ, UK. Electronic address: stella.a.cochrane@unilever.com.
authors.forename: Stella A
authors.initials: SA
authors.lastname: Cochrane
authors.affiliation: AkzoNobel NV, Arnhem, the Netherlands.
authors.forename: Josje H E
authors.initials: JHE
authors.lastname: Arts
authors.affiliation: BASF SE, GUP/PB - Z470, 67056 Ludwigshafen, Germany.
authors.forename: Colin
authors.initials: C
authors.lastname: Ehnes
authors.affiliation: Dow Europe GmbH, Bachtobelstrasse 3, CH-8810 Horgen, Switzerland.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hindle
authors.affiliation: Dow Europe GmbH, Bachtobelstrasse 3, CH-8810 Horgen, Switzerland.
authors.forename: Heli M
authors.initials: HM
authors.lastname: Hollnagel
authors.affiliation: ECETOC, Avenue Van Nieuwenhuyse 2, Box 8, B-1160 Bruxelles, Belgium.
authors.forename: Alan
authors.initials: A
authors.lastname: Poole
authors.affiliation: Sumitomo Chemical Co. Ltd. Environmental Health Science Laboratory, 3-1-98 Kasugade-Naka, Konohana-Ku, Osaka 554-8558, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suto
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
mesh_terms: D000818:Animals; D059366:Asthma, Occupational / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004784:Environmental Monitoring / Q000379:methods; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D016273:Occupational Exposure / Q000009:adverse effects*; D016272:Occupational Health; D021281:Quantitative Structure-Activity Relationship; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000175:diagnosis / Q000276:immunology / Q000503:physiopathology; D018570:Risk Assessment; D012307:Risk Factors; D014116:Toxicology / Q000379:methods
keywords: Chemical respiratory allergy; Hazard characterisation; Occupational asthma; Respiratory sensitisation; Sensitising potency; Thresholds