Evaluation of the experimental basis for assessment factors to protect individuals with asthma from health effects during short-term exposure to airborne chemicals

Figures & data

Figure 1. Approach to the identification of studies relevant to Part 1: Estimation of differential response factors on the basis of tests on healthy and asthmatic subjects under the same conditions. Relevant studies were identified from risk assessment documents and a computerized search of the peer-reviewed literature. All studies found were characterized (Table 1) and found to fulfill our criteria for quality (Table 2). Data concerning the total number of chemicals, mixtures and studies were then used as basis to estimate differential response factors.

Table 1. Characterization of the three parts of the present study.

	Part 1 EDRF	Part 2 Concentration–Response	Part 3 Benchmark concentration
Chemicals included	Any	NO2, O3, H2SO4, SO2	SO2
Form	Individual chemicals or mixtures	Individual chemicals only	Individual chemicals only
Experimental design	Only studies which both asthmatics and healthy subjects were tested under similar conditions	Studies on asthmatic and/or healthy subjects	Studies on asthmatic and/or healthy subjects
Endpoints considered	Lung function parameters, Symptoms, Inflammation markers	SRaw, FEV1	SRaw
Nature of data	Group wise	Group wise	Individual
Latest search date	18 February 2015	18 February 2015	18 February 2015
Number of studies	103	144 (healthy), 118 (asthmatics)	2 (healthy), 3 (asthmatics)

Table 2. The criteria for quality applied.

• Published in peer-reviewed journals (most not performed according to GLP).

• The same data published in two separate papers regarded as a single study.

• Methods and data well documented and scientifically sound, e.g. no conference abstracts and short letters

• Studies performed at normal room temperature (18–25 °C) and normal humidity.

• No current smokers included

• No subjects with pre-existing diseases other than asthma (e.g. COPD) included.

• No subjects with occupational or other history of heavy exposure to irritating or sensitizing air pollutants included.

• No subjects diagnosed with severe asthma disease or ongoing allergic symptoms included

Figure 2. Approach to the identification of studies for Part 2: Comparative analysis of concentration–response relationships. Studies on healthy or asthmatic subjects exposed to nitrogen dioxide, ozone, sulfuric acid or sulfur dioxide were extracted from risk assessment documents and a computerized search of the peer-reviewed literature. All of these studies were characterized (Table 1) and found to fulfill our criteria for quality (Table 2). The studies concerning data on SRaw or FEV₁ were selected for this analysis.

Table 3. Relative response by asthmatic versus healthy subjects to inhalation exposure, expressed as an overall EDRF^a.

Substance	Number of studies	Overall EDRF
Individual chemicals
Acetaldehyde	3	3
Ammonia	2	Inconclusive
Ammonium bisulfate	4	>1
Ammonium nitrate	1	Inconclusive
Ammonium sulfate	3	Inconclusive
Carbon black/particles	2	Inconclusive
Chlorine	1	2
Ferric sulfate	1	Inconclusive
Formaldehyde	3	1
Nitric oxide	1	Inconclusive
Nitrogen dioxide	14	>1
Ozone	25	>1
Sodium bisulfate	2	Inconclusive
Sodium nitrate	2	Inconclusive
Sulfur dioxide	8	>2
Sulfuric acid	14	>1
Tear gas	1	Inconclusive
2,4-/2,6-Toluenediisocyanate	1	>1
Zinc ammonium sulfate	1	1
Total, 19 chemicals	89
Mixtures and combined exposures
Carbon aerosol and sulfuric acid	1	Inconclusive
Diesel particles in ambient air (indoor, Sweden)	1	1
Environmental tobacco smoke	2	>1
Nitrogen dioxide and sulfur dioxide	1	Inconclusive
Ozone in ambient air (Los Angeles)	1	>1
Ozone and limonene	1	Inconclusive
Ozone and nitrogen dioxide	1	Inconclusive
Ozone and sulfur dioxide	1	>1
Ozone, sulfur dioxide and sulfuric acid	1	Inconclusive
Ozone and sulfuric acid	1	1
PM2.5 in urban air (Los Angeles)	3	Inconclusive
Total, 11 mixtures	14

See Appendix A: Table 1 for details.

a Calculated as the LOAEL in healthy subjects divided by the LOAEL for the same effect in asthmatics. Impaired pulmonary function, increased levels of inflammatory markers in the plasma or bronchoalveolar lavage and respiratory symptoms were the effects considered.

Figure 3. Percentage change (after/before exposure × 100) in FEV₁ and SRaw in healthy and asthmatic subjects following exposure by inhalation (oronasal breathing) to nitrogen dioxide during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 4. Percentage change (after/before exposure × 100) in FEV₁ in healthy and asthmatic subjects following inhalation exposure (mouth-only breathing) to nitrogen dioxide during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 5. Percentage change (after/before exposure × 100) in FEV₁ and SRaw in healthy and asthmatic subjects following exposure by inhalation (oronasal breathing) to ozone during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 6. Percentage change (after/before exposure × 100) in FEV₁ in healthy and asthmatic subjects following inhalation exposure (mouth-only breathing) to ozone during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 7. Percentage change (after/before exposure × 100) in FEV₁ and SRaw in healthy and asthmatic subjects following exposure by inhalation (oronasal breathing) to sulfuric acid during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 8. Percentage change (after/before exposure × 100) in FEV₁ in healthy and asthmatic subjects following inhalation exposure (mouth-only breathing) to sulfuric acid during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 9. Percentage change (after/before exposure × 100) in FEV₁ and SRaw in healthy and asthmatic subjects following exposure by inhalation (oronasal breathing) to sulfur dioxide during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 10. Percentage change (after/before exposure × 100) in FEV₁ in healthy and asthmatic subjects following inhalation exposure (mouth-only breathing) to sulfur dioxide during exercise. Each dot represents the mean response of all subjects in a particular experiment or level of exposure.

Figure 11. Benchmark concentration analysis of the increase in SRaw following exposure by inhalation to various levels of sulfur dioxide (in a chamber with a noseclip at rest). The upper and lower curves represent the best fits to the experimental data for asthmatics (Δ), and healthy subjects (o), respectively. The larger symbols depict mean values.

Table 4. Comparison of our findings to a previous assessment of differences in the responses of asthmatic and healthy subjects to irritant gases.

	Estimated differential response factor
Chemical	Young et al. (2009)	Present study (2015)
Chlorine	2	2
Formaldehyde	Approx. 1	1
Nitrogen dioxide	3–5	>1
Ozone	2	>1
Sulfur dioxide	3–4	>2
Sulfuric acid	1.3–5	>1

Young RA, Bast CB, Wood CS, Adeshina F. Overview of the standing operating procedure (SOP) for the development of Provisional Advisory Levels (PALs). Inhal Toxicol 2009;21:1–11.

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