Hypersensitivity reactions to ß-lactams: relevance of hapten-protein conjugates

B-Lactams (BL) are the drugs most frequently involved in allergic reactions. They are classified according to their chemical structure as penicillins, cephalosporins, monobactams, carbapenems, and clavams. All BL antibiotics have a BL ring that is fused to a 5-member or 6-member ring (except in monobactams) and has 1, 2 or 3 side chains (except in clavams). Differences in chemical structure mean that a wide range of BLs are recognized by the immune system, and patients may experience clinical reactions to one BL while tolerating others. Diagnosis is based on skin and in vitro testing, although both display low sensitivity, possibly because they are based on drugs or drug conjugates that are not optimally recognized by the immune system. BLs are haptens that need to bind to proteins covalently to elicit an immune response. These drugs have a high capacity to form covalent adducts with proteins through nucleophilic attack of amino groups in proteins on the BL ring. Allergenic determinants have been described for all BLs, although benzylpenicillin is the most widely studied. Moreover, formation of BL-protein adducts is selective, as we recently demonstrated for amoxicillin, which mainly modifies albumin, transferrin, and immunoglobulin heavy and light chains in human serum. Given the complexity of BL allergy, understanding the immunological mechanisms involved and optimization of diagnostic methods require multidisciplinary approaches that take into account the chemical structures of the drugs and the carrier molecules, as well as the patient immune response (AU)

Las betalactamas (BL) son los fármacos implicados más frecuentemente en reacciones alérgicas. Se clasifican según su estructura química en penicilinas, cefalosporinas, monobactamas, carbapenems y clavamas. Poseen un anillo betalactámico que, excepto en las monobactamas, está fusionado a un anillo de cinco o seis miembros y, excluyendo las clavamas, tienen 1, 2 o 3 cadenas laterales. Las diferencias en las estructuras químicas resultan en un amplio rango de BLs, que puede ser discriminado por el sistema inmune, con inducción de reacciones clínicas a una BL y tolerancia a otras. El diagnóstico está basado en pruebas cutáneas e in vitro, aunque ambas presentan una baja sensibilidad. Esto podría deberse a que los fármacos o conjugados de fármacos empleados en estos tests que no se reconocen de manera óptima por el sistema inmune. Las BLs son haptenos que necesitan de su unión covalente a proteínas para inducir una respuesta inmunológica. Estos fármacos presentan una elevada capacidad para formar aductos covalentes con proteínas mediante el ataque nucleofílico de grupos aminos de proteínas al anillo BL. Aunque la bencilpenicilina ha sido la mejor estudiada, también se han descrito determinantes alergénicos del resto de BLs. Además, la formación de los aductos BLs-proteína muestra selectividad, así se ha demostrado recientemente para la amoxicilina, que principalmente modifica la albúmina en suero (HSA), la transferrina y las cadenas ligeras y pesadas en suero humano. Dada la complejidad de la alergia a BL, el conocimiento de los mecanismos inmunológicos implicados y la optimización de los métodos diagnósticos requieren de abordajes multidisciplinares teniendo en cuenta tanto la estructura química de los fármacos y de las moléculas portadoras, como las respuestas de los pacientes (AU)

Validation study of the new criteria for sensitizer using German sensitizers of Deutschen forschungsgemeinschaft (DFG).

The globally harmonized system of classification and labeling of chemicals (GHS) was recommended by United Nations (UN) and became available in 2008 all over the world. The classification criteria for skin and airway sensitizers in GHS include evidences from animal studies, for example, OECD Guideline 406 (guinea pig maximization test, GPMT and Buhler guinea pig test) and Guideline 429 (local lymph node assay, LLNA). According to Deutschen Forschungsgemeinschaft (DFG) in Germany and European Chemical Bureau (ECB), the criteria for sensitizers also include evidences from validated animal studies. At present recognized and validated animal models for the testing of respiratory hypersensitivity are not available. In Japan, the criteria from the Japan Society for Occupational Health (JSOH) for sensitizers do not include evidences from animal studies. We revised the criteria for sensitizers of JSOH and adopted evidences of animal studies. We organized the research group for sensitizer in 2005 and reviewed the criteria of Germany, EU, GHS and so on (19 experts). The meetings were held twelve times and made the revised criteria for sensitizer which adopted animal studies. We tried to validate the criteria using 28 German sensitizers of DFG, which were not sensitizers in JSOH. We could correctly classify 24 sensitizers by our revised criteria, however, 4 sensitizers could not be classified at first. Therefore, we visited the secretariat of the committee of DFG in Freising, Germany to investigate the evidenced papers of these 4 sensitizers in October, 2008. We could find out the evidenced papers of 2, however, 2 sensitizers could not be classified at last. We could correctly classify 24 of 26 sensitizers. We concluded that our revised criteria were appropriate and that this validation study was successful.

A proposal for guideline for prevention of allergic occupational asthma in conformity with the globally harmonized system of classification and labelling of chemicals (GHS).

The use of chemical products to enhance and improve life is a widespread worldwide practice. Alongside the benefits of these products, there is also the potential of chemicals for adverse effects to people or the environment. As a result, a number of countries or organizations have developed laws or regulations over the years that require information to be prepared and transmitted to those using chemicals, through labels or Safety Data Sheets (SDS). Their differences are significant enough to result in different labels or SDS for the same product in different countries. In July 2003, United Nations (UN) recommended the globally harmonized system of classification and labelling of chemicals (GHS). We, special committee of Japanese Society of Occupational and Environmental Allergy proposed a guideline for prevention of allergic occupational asthma and sensitizers (n=60) causing occupational asthma or contact dermatitis in conformity with respiratory and skin sensitization criteria of GHS. We should propose these 60 sensitizers to the chemical industry association and governments to control, regulate and label them in each country.

How accurate are the European Union's classifications of chemical substances.

The European Commission has decided on harmonized classifications for a large number of individual chemicals according to its own directive for classification and labeling of dangerous substances. We have compared the harmonized classifications for acute oral toxicity to the acute oral toxicity data available in the RTECS database. Of the 992 substances eligible for this comparison, 15% were assigned a too low danger class and 8% a too high danger class according to the RTECS data. Due to insufficient transparency-scientific documentations of the classification decisions are not available-the causes of this discrepancy can only be hypothesized. We propose that the scientific motivations of future classifications be published and that the apparent over- and underclassifications in the present system be either explained or rectified, according to what are the facts in the matter.

Occupational asthma caused by exposure to low-molecular-weight chemicals.

Chemical agents cause approximately 40% of cases of occupational asthma (OA). Diagnosis of OA caused by chemicals relies on the demonstration of decrements in lung function at the workplace or during a controlled specific inhalation challenge to the suspect chemical agent. Evaluation of workers is accomplished best with a stepwise algorithmic approach and while the worker is symptomatic and still exposed at work. An early diagnosis followed by cessation of exposure can result in asthma remission and is likely to prevent progression to chronic disabling obstructive disease.