Respiratory hypersensitivity

Kimber, I. (1997) Toxicology of Chemical Respiratory Hypersensitivity, Taylor and Francis, London. 

It is important to remember that respiratory sensitization and asthma are related, but not identical, pathologies [31]. Asthma is a specific syndrome which appears to have genetic as well as environmental causes and there are numerous potential triggers which have been identified by immunotoxicologists [32], However, asthma is not the same disease as other respiratory hypersensitivity syndromes (sometimes referred to as chemical asthma, etc.) [33, 34], Various regulatory guidance documents have sought to deal with the latter disease entities to ensure that xenobiotics are assessed appropriately for their ability to induce immune-based pulmonary hypersensitivity reactions [35-37],... 

Holsapple, M.R et al., Assessing the potential to induce respiratory hypersensitivity, Toxicol. Sci., in press. 

Respiratory hypersensitivity is an adverse reaction in the respiratory tract driven by immune mechanisms such as IgE antibody mediated allergic responses. Other less well understood mechanisms that have an immune component are also involved in respiratory hypersensitivity. OA is one outcome of respiratory hypersensitivity. Respiratory hypersensitivity and OA to proteins are primarily mediated by IgE antibody with subsequent inflammatory cell infiltrates. This same mechanism is responsible for OA to specific LMW chemicals such as the acid anhydrides and platinum salts. However, the role for IgE mediated responses in OA to other LMW chemicals such as the isocyanates and plicatic acid is poorly defined and other mechanisms may be responsible. 

The development of respiratory hypersensitivity requires an induction phase where exposures to the sensitizer lead to an interaction with immune cells and the eventual development of specific effecter immune molecules (e.g., antibodies) and cells (e.g., T lymphocytes) [5], The induction phase can require months to years of exposure before there is a detectable immune response and/or onset of symptoms typical of respiratory hypersensitivity, including asthma. Classic IgE mediated responses have been described as Th2 cell dominant responses. A subset of CD4+ T cells known as Th2 cells push the immune response to the development of IgE and IgG4 antibodies in humans along with secretion of cytokines that attract and activate inflammatory cells such as eosinophils. 

In summary, chemical contact sensitization will be favored by the selective activation of Thl and Tel cells, whereas immediate type hypersensitivity reactions such as chemical respiratory hypersensitivity are apparently associated with the preferential activation of Th2 (and possibly Tc2) type cells. 

Sarlo, K. and Ritz, H.L., Predictive assessment of respiratory sensitizing potential in guinea pigs, in Toxicology of Chemical Respiratory Hypersensitivity, Kimber, I., and Dearman, R.J., Eds., Taylor and Francis, London, pp. 107, 1997. 

Rattray, N. J. et al, Induction of respiratory hypersensitivity to diphenylmethane-4,4 -diiso-cyanate (MDI) in guinea pigs. Influence of route of exposure. Toxicology, 88, 15, 1994. 

Pauluhn, J. et al., Respiratory hypersensitivity to diphenylmethane-4,4 -diisocyanate in guinea pigs Comparison with trimellitic anhydride. Inhal. Toxicol., 11, 187, 1999. 

Pauluhn, J., Eidmann, P. and Mohr, U., Respiratory hypersensitivity in guinea pigs sensitized to 1,6-hexamethylene diisocyanate (HDI) Comparison of results obtained with the monomer and homopolymers of HDI. Toxicology, 171, 147, 2002. 

The general objectives for assessing the sensitization potential of a substance are to examine whether there are indications from human experience of skin allergy or respiratory hypersensitivity following exposure to the substance, and whether the substance has a skin sensitization potential based on tests in animals. 

The likelihood that a substance will induce skin sensitization or respiratory hypersensitivity in humans who are exposed to this substance is determined by several factors including the route, duration and magnitude of exposure, and the potency of the substance (EC 2003). 

There is evidence that dose-response relationships exist for both skin sensitization and respiratory hypersensitivity, although these are frequently less well defined in the case of respiratory hypersensitivity (EC 2003). The dose of a substance required to induce sensitization in a previously naive subject or animal is usually greater than that required to elicit a reaction in a previously sensitized individual therefore, the dose-response relationship for these two phases will differ. Elicitation responses depend on several factors, among which are potency of the allergen and exposure conditions. Appropriate dose-response data can provide important information on the potency of the substance under evaluation. For sensitizers it is considered prudent to assume that a threshold cannot be identified, i.e., it is not possible to identify an elicitation dose or concentration of a sensitizing substance below which adverse effects are unlikely to occur in people already sensitized to a substance (EC 2003). 

Certain well-known groups of chemicals such as isocyanates and acid anhydrides are currently considered to cause respiratory hypersensitivity unless proved otherwise (EC 2003). 

Pauluhn, J. Mohr, U. (1994) Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4 -diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate. Toxicology, 92, 53-74... 

If there is evidence in humans that the substance can induce specific respiratory hypersensitivity and/or... 

Evidence that a substance can induce specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated. 

Clinical history should include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history should also include a note of other allergic or airway disorders from childhood, and smoking history. 

At present recognized animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, animal testing may be used, e.g. a modification of the guinea pig maximization test for determination of relative allergenicity ofproteins. However, these tests still needfurther validation. 

If there is human evidence that the individual substance induces specific respiratory hypersensitivity, and/or... 

Kimber I. The role of the skin in the development of chemical respiratory hypersensitivity. Toxicol Lett 1996 86(2-3) 89-92. 

Becher R, Hongslo JK, Jantunen MJ, Dybing E Environmental chemicals relevant for respiratory hypersensitivity The indoor environment. Toxicol Lett 1996 86 155-162. 

It is apparent that both chemicals and proteins are able to cause workrelated asthma. While the focus of this book is primarily upon respiratory hypersensitivity induced by chemicals, it is recognized that there exists a need to identify those... 

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