Asthmatics as a susceptible population in health risk assessment of airborne chemicals

Asthma is a common chronic airway disease and about 235-300 million individuals of all ages are affected by the disease around the world. A precondition of asthma has been suggested to increase individual susceptibility to acute exposure from airborne irritant chemicals. In the health risk assessments of such chemicals, acute guideline values are derived to guide in preparedness and in emergency response, and to protect the general population, including susceptible subpopulations such as asthmatics. Experimental data on susceptible subpopulations are lacking for many chemicals and default inter-individual assessment factors (AFs) have been applied in the derivation of guideline values. However, the scientific basis for these default AFs in regard to asthmatics has been inadequate. The aims of this thesis were threefold. First, to study the extent to which experimental data regarding chemicals tested on asthmatics are included in the derivation of different sets of acute to short-term guideline values, and second, to determine whether there is a general difference in the airway response between healthy and asthmatic individuals, and whether current AFs for inter-individual variability provide sufficient protection for asthmatics. Last, to gain more knowledge on the susceptibility of asthmatics by measuring the airway response to chlorine in naive and allergen-sensitized mice. In Paper I, the analysis of how asthmatics are considered in the derivation of Acute Exposure Guideline Levels (AEGLs) reveals that only 14 of 250 chemicals in the support documents had been tested on asthmatic subjects in experimental studies. A comparison between the AEGL support documents and nine other sets of acute to short-term guideline values shows that all of them were incomplete with respect to experimental data on asthmatics. In Paper II, experimental studies in which both healthy and asthmatic subjects were tested under the same conditions served as the basis for evaluating the lowest observed adverse effect concentrations (LOAECs) for healthy subjects and for asthmatic subjects. The ratios of these LOAECs were calculated and presented as estimated differential response factors (EDRFs). We found evidence of higher sensitivity among asthmatics (EDRF > 1) to 8 of 19 tested chemicals, and to 3 of 11 mixtures. Thereafter, concentration–response relationships confirmed the higher sensitivity of asthmatics to sulfuric acid and sulfur dioxide, and the Benchmark concentration (BMC) analysis of sulfur dioxide indicated a nine fold higher sensitivity among asthmatics. In Paper III, the consideration of asthmatics in the Derived NoEffect Levels (DNEL), developed under the European Union (EU) registration, evaluation, authorization and restriction of chemicals (REACH) legislation revealed that only 14 registered chemicals had been tested on asthmatics in experimental studies. Many of the DNELs for acute inhalation were higher than our estimated overall LOAEC or no observed adverse effect concentrations (NOAECs) in asthmatics, indicating a low or no safety margin. The experimental asthma model in Paper IV showed that exposure to 80 ppm of chlorine in naive (but not OVA-sensitized) mice resulted in increased airway responsiveness and elevated numbers of neutrophils in the bronchoalveolar lavage fluid. Concentrationdependent reductions in respiratory frequency were seen in both groups. These results do not support an increased susceptibility to chlorine among mice with induced eosinophilic airway inflammation. Exclusion of asthmatics in the derivation of acute to short-term guideline values may interfere with trustful and efficient health-protective actions. The use of an AF of 10 when there is a lack of experimental data on asthmatics may be adequate to protect this subpopulation from the deleterious respiratory effects of airborne chemicals. POPULARVETENSKAPLIG SAMMANFATTNING Idag lever ungefar 235-300 miljoner individer med astma i varlden och antalet har okat de senaste artiondena. Personer i alla aldrar och samhallsklasser drabbas och i Sverige har ungefar en av tio sjukdomen. Astma ar en luftvagssjukdom som kannetecknas av inflammation i luftvagarna och episoder med svarigheter att andas, s.k. astmaattacker. Olika faktorer som fysisk anstrangning och exponering for allergener och luftburna kemikalier kan utlosa en astmaattack. Exponering for luftburna irriterande kemikalier kan ske pa arbetsplatser, men allmanheten kan ocksa exponeras i samband med transportoch industriolyckor. Halsoriskbedomningar genomfors for att veta nar man behover vidta sakerhetsatgarder i samband med exponering for kemikalier. Som ett led i riskbedomningen kan riktvarden beraknas. Riktvarden motsvarar den maximala kemikaliekoncentration vid vilken inga negativa halsoeffekter uppstar hos individer, och de kan beraknas for olika exponeringsvagar, exponeringstider och for olika grupper i samhallet. Nar det saknas information om hur en kemikalie paverkar astmatiker anvander man data fran friska forsokspersoner eller forsoksdjur. For att kompensera for den osakerhet som detta innebar anvands en extra sakerhetsmarginal, en s.k. bedomningsfaktor eller sakerhetsfaktor. Syftet med den har avhandlingen var; 1) att undersoka om astmatiker ar skyddade fran akut exponering for luftburna kemikalier bade pa och utanfor arbetsplatsen, 2) att studera hur stor skillnaden ar i kanslighet mellan astmatiker och friska individer nar de exponeras akut for luftburna kemikalier, och, 3) att fa mer kunskap om astmatikers kanslighet genom att experimentellt studera halsoeffekter fran kemikalieexponering i en astmamodell pa moss. For att ta reda pa hur myndigheter och organisationer i olika lander och pa EU-niva har tagit hansyn till astmatiker i framtagandet av halsobaserade akuta riktvarden analyserades halsoriskbedomningar i delarbete I och III. I delarbete II analyserades data fran tidigare experimentella studier, gjorda pa astmatiska och friska individer, for att ta reda pa hur stor skillnaden ar i kanslighet mellan grupperna. I den experimentella modellen (delarbete IV) exponerades bade moss med allergen-inducerad luftvagsinflammation och friska moss for klorgas i olika koncentrationer. Effekter pa andningsfrekvens och lungfunktion samt inflammationssvar och lungskador analyserades. Resultaten visar att man inte tar tillracklig hansyn till astmatiker vid framtagandet av akuta riktvarden och att riskbedomare inte anvander sig av alla tillgangliga experimentella data pa astmatiker som underlag i halsoriskbedomningar. Astmatiker visade sig vara kansligare an friska for 11 av 30 irriterande kemikalier och blandningar och de var upp till nio ganger kansligare an friska vid exponering for svaveldioxid. Den anvanda djurmodellen visar inte nagon okad kanslighet mot klorgas hos djur med allergisk luftvagsinflammation. Expertgrupper och riskbedomare bor systematiskt ta astmatikers eventuella kanslighet i beaktande i framtagandet av akuta riktvarden for luftburna amnen. Utifran vara data foreslar vi anvandandet av en sakerhetsfaktor pa 10 for att skydda astmatiker nar experimentella data fattas for denna grupp. LIST OF SCIENTIFIC PAPERS This thesis is based on the following articles. They will be referred to as Paper I-IV. I. Johansson M, Johanson G, Oberg M. 2012. How are asthmatics included in the derivation of short-term values for emergency planning and response? Regul. Toxicol. Pharmacol. 63:461-470 II. Johansson M, Johanson G, Oberg M. Evaluation of the experimental basis for assessment factors to protect individuals with asthma from health effects during short-term exposure to airborne chemicals. Crit. Rev. Toxicol. (E-pub ahead of print http://dx.doi.org/10.3109/10408444.2015.1092498) III. Johansson M, Johanson G, Oberg M, Schenk, L. Does industry take the susceptible subpopulation of asthmatic individuals into consideration when setting Derived No-Effect Levels (DNELs)? (Submitted for publication) IV. Johansson M, Gustafsson A, Johanson G, Oberg M. Comparison of airway response in naive and ovalbumin sensitized mice during short-term inhalation exposure to chlorine. (Manuscript)