Aims: To investigate quantitatively, relationships between chemical structure and reported occupational asthma hazard for low molecular weight (LMW) organic compounds; to develop and validate a model linking asthma hazard with chemical substructure; and to generate mechanistic hypotheses that might explain the relationships. Methods: A learning dataset used 78 LMW chemical asthmagens reported in the literature before 1995, and 301 control compounds with recognised occupational exposures and hazards other than respiratory sensitisation. The chemical structures of the asthmagens and control compounds were characterised by the presence of chemical substructure fragments. Odds ratios were calculated for these fragments to determine which were associated with a likelihood of being reported as an occupational asthmagen. Logistic regression modelling was used to identify the independent contribution of these substructures. A post-1995 set of 21 asthmagens and 77 controls were selected to externally validate the model. Results: Nitrogen or oxygen containing functional groups such as isocyanate, amine, acid anhydride, and carbonyl were associated with an occupational asthma hazard, particularly when the functional group was present twice or more in the same molecule. A logistic regression model using only statistically significant independent variables for occupational asthma hazard correctly assigned 90% of the model development set. The external validation showed a sensitivity of 86% and specificity of 99%. Conclusions: Although a wide variety of chemical structures are associated with occupational asthma, bifunctional reactivity is strongly associated with occupational asthma hazard across a range of chemical substructures. This suggests that chemical cross-linking is an important molecular mechanism leading to the development of occupational asthma. The logistic regression model is freely available on the internet and may offer a useful but inexpensive adjunct to the prediction of occupational asthma hazard.

https://oem.bmj.com/content/oemed/62/4/243.full.pdf

Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds.

Diisocyanate asthma: clinical aspects and immunopathogenesis.

Background Determination of polyisocyanates is important because they are a major contributorofexposuretotheisocyanatefunctionalgroupinmanyworkplaceenvironments and are capable of inducing sensitization and asthma. However, with multiple different measurement metrics in use, comparison of isocyanate exposure data between studies and development of occupational exposure limits (OELs) for polyisocyanates is difficult. Methods An analysis of existing problems in the measurement and regulation of isocyanates is presented based on the published analytical, toxicological, and regulatory literature, and the authors’ own analytical data and experience with isocyanates. Results This analysis supports a need for standardization of isocyanate measurement metrics and provides a framework for the development of an OEL for polyisocyanates. Conclusions Thetotalisocyanategroup(mgNCO/m 3 )isrecommendedasthemostfeasible and practical metric (unit) by which to express polyisocyanate exposures for research, control, and regulatory purposes. The establishment of a comprehensive isocyanate OEL that simplifies the current agent-by-agent approach and expands coverage to polyisocyanates is also recommended. Am. J. Ind. Med. 46:480–491, 2004. 2004 Wiley-Liss, Inc.

/pdf/polyisocyanates-in-occupational-environments-a-critical-6jlz7mlm08.pdf

Polyisocyanates in Occupational Environments: A Critical Review of Exposure Limits and Metrics

The development of occupational asthma (OA) is likely to result from the complex interaction of environmental and host factors. This article addresses a series of issues relating to the multiple environmental factors that could affect the initiation of OA, including the intrinsic characteristics of causative agents, as well as the influence of the level, mode and route of exposure. Although the clinical and pathological features of OA caused by low molecular weight agents resemble those of immunoglobulin (Ig)E-mediated asthma, the failure to detect specific IgE antibodies against most of these agents and/or poor association with disease status have resulted in intense speculation about alternative or complementary physiopathological mechanisms leading to airway sensitisation. In this contribution, the roles of specific immunoglobulin E and G antibodies, cell-mediated immunity and inflammatory effector cells are critically reviewed. Recent advances in the characterisation of the molecular interactions between chemical sensitisers and human airway proteins provide promising avenues for elucidating the immunological basis of occupational asthma caused by low molecular weight agents.

https://erj.ersjournals.com/content/erj/22/2/364.full.pdf

Pathogenesis of occupational asthma

Summary Background Anaphylaxis to mannitol present naturally in pomegranate and cultivated mushroom in a sensitized subject has been described recently, and an IgE-mediated mechanism to this sugar alcohol has been proposed. The same subject also experienced severe allergic reactions to a chewable pharmaceutical (cisapride drug). Objective The purpose of the study was to identify allergenic component in the pharmaceutical preparation, and also, to understand the mechanism of immediate hypersensitivity to mannitol. Methods Methodology involved skin prick tests (SPTs), high-performance liquid chromatographic (HPLC) analysis of pharmaceutical preparations, separation of mannitol by Ca 11 -ion-moderated cation-exchange chromatography, preparation of alditol–protein conjugates by reductive amination, SPT using the conjugates, hapten affinity purification of the allergic serum on D-mannitol–keyhole limpet haemocyanin (KLH)–Sepharose CL-6B, and detection of serum mannitol-specific IgE by ELISA. Results Component testing by SPT, and HPLC analysis of various pharmaceuticals indicated that the excipient mannitol is the causative allergen. Mannitol separated from Cisapid MPS showed allergenic activity by SPT. Among the several conjugates tested by SPT, D-mannitol–bovine serum albumin and D-mannitol–KLH showed positive weal/flare reaction, demonstrating the presence of cell-bound mannitol-specific IgE in vivo. Negative results with D-glucitol, D-galactitol, mesoerythritol, and L-mannitol protein conjugates clearly showed that the mannitol-specific human IgE is very specific to the D-isomer of mannitol. ELISA using the hapten affinity-purified allergic serum was positive, demonstrating the presence of mannitol-specific serum IgE in the allergic subject. Conclusion Mannitol, which is widely used as a food and drug additive (excipient), can rarely cause IgE-mediated anaphylaxis. This study is the first one to demonstrate the presence of mannitolspecific human IgE in a sensitized allergic subject to validate an IgE-mediated hypersensitivity mechanism for mannitol.

Anaphylaxis to excipient mannitol: evidence for an immunoglobulin E-mediated mechanism

Objective The objective of this review is to provide current approaches to gain increased understanding of the molecular basis of chemical allergenicity. Chemical allergy refers to an allergic reaction to a low molecular weight agent (ie, Data Sources Data were obtained from published clinical reports and from the Documentation of Threshold Limit Values (1998) published by the American Congress of Governmental Industrial Hygienists. Results In vitro studies indicate the stoichiometric reaction of some chemical allergens with glutathione and the subsequent transfer of the allergen from glutathione to other nucleophiles. Computer-generated structure-activity relationship models have been developed for chemicals that induce respiratory allergy. The models, based on physicochemical properties of the agents, have high sensitivity and specificity. Conclusions The structure-activity relationship model suggests that chemical binding is the essential feature of chemical allergens. Their in vivo reactions with thiols may result in glutathione deficiency with consequent alteration in cellular reduction-oxidation (redox) status, release of cytokines, and promotion of the T helper cell 2 phenotype. Prevention of permanent disease is dependent on periodic medical surveillance of affected workers. When detected early, the disease can frequently be reversed.

Meryl H. Karol

Papers

Cell and molecular biology of chemical allergy