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Letter
Decreased Human Respiratory Absorption Factors of Aromatic Hydrocarbonsat Lower Exposure Levels: The Dual Effect in Reducing Ambient Air Toxics
Zhonghui Huang, Yanli Zhang, Qiong Yan, Zhaoyi Wang, Zhou Zhang, and Xinming WangEnviron. Sci. Technol. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.estlett.7b00443 • Publication Date (Web): 23 Oct 2017
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Just Accepted
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1
Decreased Human Respiratory Absorption Factors of Aromatic Hydrocarbons 1
at Lower Exposure Levels: The Dual Effect in Reducing Ambient Air Toxics 2
Zhong-Hui Huang,†,‡
Yan-Li Zhang,†,§
Qiong Yan,‖
Zhao-Yi Wang,†,‡
Zhou 3 Zhang,
† and Xin-Ming Wang*,†,§
4
†State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of 5
Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, 6 Chinese Academy of Sciences, Guangzhou 510640, China 7
‡University of Chinese Academy of Sciences, Beijing 100049, China 8
§Center for Excellence in Urban Atmospheric Environment, Institute of Urban Environment, 9
Chinese Academy of Sciences, Xiamen 361021, China 10
ǁDepartment of Respiratory Diseases, Guangzhou No.12 People’s Hospital, Guangzhou 11 510620, China 12
13
14
15 16
17
18
19
20
*Corresponding author: 21
Dr. Xinming Wang 22
State Key Laboratory of Organic Geochemistry 23
Guangzhou Institute of Geochemistry, Chinese Academy of Sciences 24
Guangzhou 510640, China 25
Tel.: +86-20-85290180; fax: +86-20-85290706. 26
E-mail: [email protected] 27
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ABSTRACT 28
Respiratory absorption factors (AFs) are important parameters for assessing human health 29
risks of long-term inhalation exposure to low-level hazardous air pollutants. However, it is 30
uncertain whether previously measured respiratory AFs for high-level exposures could be 31
directly applied. Here we measured real-time respiratory AFs using proton transfer reaction 32
time-of-flight mass spectrometry (PTR-TOF-MS) for 50 fifty subjects (aged 20-30; 24 33
females and 26 males) exposed in a normal office room with aromatic hydrocarbons (AHs) at 34
concentration levels of several part per billion by volume (ppbv). The mean respiratory AFs 35
of benzene, toluene, and C8-aromatics (ethylbenzene and xylenes) from all subjects were 36
28.2%, 63.3%, and 66.6%, respectively. No gender difference in the respiratory AFs of AHs 37
was observed. Correlation analysis revealed that exposure concentration, rather than 38
physiological parameters like body mass index (BMI) or body fat ratio (BFR), was the 39
dominant factor influencing the AFs of AHs. The results also demonstrated that respiratory 40
AFs decreased in a logarithmic way when lowering exposure levels of AHs. The decreased 41
respiratory AFs at lowered exposure levels suggest the dual effect of reducing ambient air 42
toxics like AHs on lowing human inhalation intake. 43
44
Keywords: Inhalation exposure; respiratory absorption factors; volatile organic compounds 45
(VOCs); hazardous air pollutants; PTR-TOF-MS 46
47
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� INTRODUCTION 55
There has been an increasing attention about volatile organic compounds (VOCs) in ambient 56
air, not only for their roles in forming tropospheric ozone and secondary organic aerosols 57
(SOA),1-4 but also for their potential carcinogenic and non-carcinogenic health effects on the 58
human population. Exposure to hazardous VOCs might be associated with respiratory, 59
cardiovascular, and neurological diseases including asthma, chronic obstructive pulmonary 60
disease (COPD), and leukemia.5-12 The inhalation intake of toxic VOCs, however, depends 61
not merely on the ambient levels of VOCs. Respiratory absorption factors (AFs), which 62
denote the percentages of inhaled toxicants retained authentically inside the human body, are 63
considered to be indispensable parameters in assessing daily intakes and health risks due to 64
exposure to toxic VOCs.13-18 65
The air we breathe contains a diverse range of low-level VOCs that can be taken up by the 66
body, and health endpoints related to long-term low-level exposure of air toxics is a 67
challenging issue in environmental health. Yet very little is known about the respiratory AFs 68
of low-level VOCs in indoor or outdoor environments. Results from the Total Exposure 69
Assessment Methodology (TEAM) studies conducted in the 1980’s indicated that higher 70
fractions of inhaled benzene concentrations are absorbed at very low doses.19, 20 Based on a 71
wide range of earlier studies concerning respiratory AFs of VOCs in very high levels (tens of 72
ppmv or even higher),21 AFs were assumed to be 90%,14-17, 22-25 100%18, 26-38 or most recently 73
to be 50-60%39, 40 when assessing health risks of inhalation exposure to toxic VOCs. It is 74
questionable whether these AFs can be applied to low-level exposure situations. Moreover, 75
AFs are regarded as constant to simplify the inputs in pharmacokinetic models studying the 76
fate of exogenous VOCs within the human body.41-44 In essence, these AFs are more likely to 77
be variable as they are affected by a multitude of factors including exposure concentrations, 78
physicochemical behaviors of VOCs and individual human physiological conditions.45 Hence 79
it is necessary to determine respiratory AFs of toxic VOCs particularly in the low-level 80
exposure environments. 81
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The most common aromatic hydrocarbons (AHs), namely benzene, toluene, ethylbenzene, 82
and xylenes (BTEX), were chosen as typical toxic VOCs in the present study. BTEX are a 83
major class of hazardous air pollutants: benzene is a well-known carcinogen causing leukemia, 84
and TEX may deteriorate developmental, nervous, and heart and blood vessel systems.13, 46 85
Additionally, BTEX are ubiquitous in both indoor and outdoor environments, particularly in 86
developing countries.47-53 Even at background sites in China ambient benzene levels might 87
exceed the limit set by European Union (EU).54 In this study, fifty volunteers were asked to 88
stay in a normal office room, and by using a homemade online breath sampling device 89
coupled to a proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS), 90
real-time respiratory AFs were measured for all subjects exposed to indoor AHs at several 91
part per billion by volume (ppbv). The purposes of this study are: 1) to check if there is a 92
gender difference in the respiratory AFs of AHs; 2) to explore the relationship between AFs 93
and exposure levels under low-level exposure situations; and 3) to investigate if physiological 94
factors, such as body mass index (BMI) and body fat rate (BFR), influence the respiratory 95
AFs. 96
� MATERIALS AND METHODS 97
Subjects. First phase test: a total of fifty young volunteers, who were then all graduate 98
students studying in the Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, 99
participated in this study. Every test subject was required to stay in a well-ventilated normal 100
office room for about half an hour during the test with PTR-TOF-MS. It should be noted that 101
this was not a human toxicity test because none of the BTEX were injected into the office 102
room. All subjects gave written informed consent prior to participation in the study. Subjects 103
completed a brief questionnaire concerning needed information regarding their gender, age, 104
height, weight, BMI, BFR, smoking/drinking status, and personal/familial past medical 105
history. These fifty subjects included 26 males and 24 females, aged 20-30 years old. They 106
were all non-smokers and non-drinkers. Demographic data of the subjects represented in the 107
study are summarized in Table S1 (Supporting Information). 108
Second phase test: in order to further verify the relationships between exposure 109
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concentrations and AFs of BTEX, one male and one female subjects were randomly selected 110
from volunteers participating the first phase test. They were asked to stay 4 h per day in the 111
same office room over 3 days for more tests of AFs with the variation of BTEX largely due to 112
ventilation. 113
Online Breath Sampling and Measurement. A homemade online breath sampling 114
device was used for sampling air inhaled and exhaled by subjects. Detailed description of the 115
sampling device can be found in our previous study.21 There is, however, an improvement 116
that a Swagelok plug valve was added between the left end of the tube and the nose interface 117
in the current study. 118
A commercial high-sensitivity PTR-TOF-MS (model 2000; Ionicon Analytik GmbH, 119
Innsbruck, Austria) was deployed to measure BTEX levels in the breath samples. The 120
measurement principle of PTR-TOF-MS has been described elsewhere in detail.55-57 The 121
PTR-TOF-MS acquired data at a 0.5 Hz time resolution with H3O+ reagent ion. The drift tube 122
of the instrument was operated at a voltage of 610 V, pressure of 2.20 mbar, and temperature 123
of 60°C, with an E/N ratio of about 139 Townsend (Td) (where E is the electric field strength 124
and N is the number density of a neutral gas; 1 Td = 10−17 V cm2). 125
Detailed online breath sampling and measurement steps were described in our 126
previous study.21 Briefly, indoor air, which was the air inhaled by subjects, was firstly 127
sampled and measured through the online breath sampling device. During the ensuing exhaled 128
air measurements, the subject steadily exhaled alveolar air into the sampling device, and then 129
closed the plug valve right after a complete expiration. The plug valve was blocked until the 130
exhaled air in the buffer tube was exhausted and hereafter the indoor air was extracted and 131
measured for several minutes. According to the above operating steps, the inhaled and 132
exhaled air for each subject was continuously measured to determine their respiratory AFs as: 133
�� =�����
��×100% (1) 134
where Ci and Ce (ppbv) were the concentrations of the target compound in the inhaled and 135
exhaled air, respectively. Isoprene was used as a breath tracer for identifying the expiratory 136
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and inspiratory phases in this study.21 137
Quality Assurance and Quality Control. Target VOCs were identified based on their 138
exact mass to charge ratio (m/z) and quantified by external calibration methods. Mass 139
calibration was performed using two ion peaks with known exact masses: hydronium ion 140
isotope (H318O+; m/z 21.022) and protonated 1, 2, 4-trichlorobenzene ((C6H3Cl3)H
+, m/z 141
180.937). The isomeric ethylbenzene and xylenes, all with a molecular mass of 106 amu, 142
cannot be distinguished by PTR-TOF-MS, and thus these C8-aromatics were reported as their 143
sum. 144
Background levels for target compounds were determined by introducing zero air into the 145
instrument. Multi-point calibration of the PTR-TOF-MS was carried out before the breath air 146
measurement using VOC standard mixtures (including isoprene, benzene, toluene, o-xylene) 147
that were dynamically diluted to five levels (2, 5, 10, 15, and 20 ppbv) from a certified 148
standard gas mixture (Ionicon Analytik GmbH; ~1 ppmv). The linear correlation coefficients 149
(R2) of calibration curves were 0.996–0.999 for BTEX compounds. Their sensitivities, 150
indicated by the ratio of normalized counts per second (ncps) to the levels of BTEX in ppbv, 151
were 27, 35, and 40 ncps/ppbv for benzene, toluene and C8-aromatics, respectively. The 152
method detection limits (MDL) for benzene, toluene, and C8-aromatics in 2 s integration time 153
were 0.055, 0.044, and 0.039 ppbv, respectively. The measurement precisions and accuracies 154
were determined by repeated analysis of a standard mixture (1 ppbv) seven times. The relative 155
standard derivations for BTEX were all < 5%, and the accuracies of BTEX were all within ± 156
10%. BTEX will accept a proton from H3O+, but their reaction with (H2O)2H
+ is 157
thermodynamically unavailable. Previous studies have shown no significant humidity 158
dependence on their sensitivities.58-61 To re-confirm this, three levels of standard mixtures in 159
the range of 0-10 ppbv were prepared at relative humidity (RH) of 20% and 95%, respectively. 160
RH was controlled as per the details provided in Kumar and Sinha.62 As shown in Figure S1, 161
no significant differences in the BTX sensitivities (ncps/ppbv) were observed between the 162
standard mixtures at RH of 20% and 95% probably due to a high proportion of H3O+ ion in 163
the drift tube with a high E/N ratio. Thus humidity effects in breath samples can be ignored 164
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when measuring BTEX by PTR-TOF-MS in the present study. 165
Statistical analysis. The Student’s t-test in the statistical software package SPSS (Version 166
19) was used to examine statistical differences in measured concentration levels. Two-tailed 167
tests of significance were used, and p < 0.05 indicated statistical significance. It was also used 168
as critical value for significant correlation. 169
� RESULTS AND DISCUSSION 170
Real-time AFs of BTEX. The measured BTEX exposure levels ranged from 0.19–3.26 171
ppbv for benzene, 0.35–8.72 ppbv for toluene, and 0.31–6.84 ppbv for C8-aromatics in the 172
first phase test. Five sets of inhaled and exhaled air for each subject were successively 173
measured to acquire the respiratory AFs of BTEX. The average respiratory AFs and their 174
standard deviations (SD) of benzene, toluene, and C8-aromatics from all 50 subjects were 175
28.2% (SD = 10.9%), 63.3% (SD = 12.7%), and 66.6% (SD = 10.6%), respectively (Figure 176
S2). The mean respiratory AFs of benzene was much lower than previously assumed or 177
measured 90%,14-17, 22-25 100%18, 26-38 or 50-60%21, 39, 40; for toluene and C8-aromatics, the 178
mean values were near that measured in our previous study,21 but still much lower than 179
previously assumed values of 90%14-17, 22-25 or 100%18, 26-38 when assessing inhalation health 180
risks. 181
The mean respiratory AFs of benzene, toluene and C8-aromatics were 28.0%, 57.6% and 182
63.4% for the female subjects; and 28.5%, 69.1% and 69.7% for the male subjects, 183
respectively. No significant difference (p > 0.05) was observed in the respiratory AFs between 184
the female and male subjects, implying no gender difference in the respiratory AFs. In our 185
previous preliminary tests with 7 subjects,21 the 3 female subjects had significantly higher 186
respiratory AFs of BTEX than the 4 male ones (p < 0.05). Probably the small numbers of 187
subjects for the test in our previous study statistically bias the gender difference discussion. 188
Influencing Factors of AFs. Three aspects of factors, i.e., physicochemical properties of 189
VOCs, individual human physiology, and environmental factors, govern the respiratory 190
AFs.45 In this study we only focused on BTEX and their mean respiratory AFs appeared to 191
increase with molecular weight, reflecting the influence of physicochemical properties of 192
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these compounds such as lipophilicity, solubility in blood, and blood/air partition 193
coefficients.41, 63, 64 194
Humans are incredibly diverse, and common individual physiological parameters such as 195
gender, age, health state, BMI, and BFR needed to be seriously considered for discerning the 196
crucial influencing factors of AFs.41, 65, 66 As mentioned above, gender was not a key factor 197
affecting the AFs. Regarding age and health state, all volunteers were healthy young people 198
aged 20-30 without any past personal or familial medical history (Table S1). BMI, defined as 199
a person’s weight in kilograms divided by the square of one’s height in meters (kg/m2), is a 200
universal standard introduced by the World Health Organization for assessing the body fat 201
levels and health state. BFR is another parameter of reflecting the percentage of body fat 202
content to the body weight (Table S1). Figure 1 shows scatter plots of the respiratory AFs 203
versus BMI and BFR. No significant correlations between AFs and BMI/BFR were observed, 204
either for all subjects or for female and male subjects individually. 205
Environmental factors including pre-exposure concentration, exposure concentration and 206
duration, also influence the absorbed dose of toxic VOCs.65, 67 Because all subjects were then 207
graduate students working and living in the same institute campus, they should have quite 208
similar pre-exposure experience. During our test, subjects were exposed to different levels of 209
BTEX in the normal office room due diurnal variations. The correlations between the AFs 210
and exposed BTEX concentrations for all volunteers are shown in Figure 2a-c. The highly 211
significant log-based (p < 0.001) correlations between the AFs and exposure levels of BTEX 212
suggested that exposure levels rather than individual physiological factors were responsible 213
for the AFs, consistent with the conclusions in some previous studies.65, 68-70 214
Relationship between Exposure Levels and AF. The second phase test with just one male 215
subject and one female subject for extensive measurements would eliminate the effects of 216
inter-individual physiological variations. The relationships between exposure levels and AFs 217
for the two subjects are illustrated in Figure 2d-i, confirming the highly significant 218
logarithmic correlations for all subjects as discussed above. 219
The mechanism for the logarithmic relationship remains unexplained so far. But the 220
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phenomenon is reasonable because at low-exposure levels the inhalation absorption process 221
of BTEX might be similar to the Langmuir isothermal adsorption process of VOCs on the 222
surface of adsorbents, in which the adsorption efficiencies would increase with the elevated 223
concentrations of VOCs until reaching a relatively stable value when concentrations of VOCs 224
exceed a certain level.71 As showed in Figure S3, the relationships between exposure levels 225
and AFs could be well fitted with Langmuir adsorption isotherms. 226
Our results, as showed in Figure 2, demonstrated that if BTEX concentrations go down to 227
about 2 ppb or even lower, respiratory AFs decrease rapidly, implying the dual effect in 228
lowering human inhalation dose by reducing BTEX concentration in ambient air: inhalation 229
uptake would further reduced by lower AFs at lower exposure levels. This is very important 230
for some air pollutants, such as benzene, that are carcinogenic to humans and no safe level of 231
exposure can be recommended, although the inhalation minimal risk level (MRL) of 3 ppbv 232
was recommended by the United States Environmental Protection Agency (USEPA) for 233
benzene,72 and an annual limit of 5 µg/m3 (or 1.6 ppbv at 25°C and 1 atm) was established by 234
the EU for benzene in ambient air.73 From our study, as showed in Figure 2a, if benzene 235
levels decrease from 1.0 ppbv to 0.5 ppbv, its AFs would decrease from ~70% to ~40%, 236
consequently the internal intakes would decrease by ~70%, more than the 50% expected due 237
to a decrease in exposure levels alone. 238
We observed that the AFs decreased in a logarithmic way with decreasing the exposure 239
levels of BTEX. The finding is valuable for rationally assessing human health risks of 240
long-term inhalation exposure and for evaluating the effects of control measures for BTEX. 241
Nonetheless, since in this study all subjects shared similar demographic characteristics (age, 242
weight, height, and etc.) and lived in the same area, it is of concern whether our conclusions 243
can be applied to the general population and this needs to be verified with more extensive 244
study in the future. 245
246
� ASSOCIATED CONTENT 247
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Supporting Information 248
Demographic data of subjects in this study (Table S1); Normalized sensitivities at 249
different relative humidity of 20% and 95% for benzene, toluene and o-xylene. Slopes 250
(i.e. sensitivities) are indicated by mean values ± standard errors (Figure S1); 251
Respiratory AFs of benzene, toluene, and C8-aromatics from fifty test subjects. The 252
columns and their error bars represent the mean values and standard deviations of the 253
respiratory AFs of BTEX, respectively (Figure S2); Extended Langmuir isotherms 254
between respiratory AFs and exposure concentrations of benzene (open squares), 255
toluene (open cycles), and C8-aromatics (open triangles) collected from all (blue, a-c), a 256
male (cyan, d-f) and a female (green, g-i) subjects, respectively. Curve-fitting equations 257
and their correlation coefficient (R2) and significance levels (p) were also presented 258
(Figure S3). 259
260
� AUTHOR INFORMATION 261
Corresponding Author 262
*Phone: +86-20-85290180. Fax: +86-20-85290706. E-mail: [email protected]. 263
ORCID 264
Zhong-Hui Huang: 0000-0003-0144-0852 265
Yan-Li Zhang: 0000-0003-0614-2096 266
Xin-Ming Wang: 0000-0002-1982-0928 267
Notes 268
The authors declare no competing financial interest. 269
270
� ACKNOWLEDGMENTS 271
This work was financially supported by the Natural Science Foundation of Guangdong (Grant 272
No. 2016A030313164), the Health and Family Planning Commission of Guangzhou 273
Municipality (Grant No. 20161A010050), and the Natural Science Foundation of China 274
(Grant No. 41530641/41571130031). The authors would like to express their sincere thanks 275
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to volunteers in Guangzhou Institute of Geochemistry, Chinese Academy of Sciences for their 276
supports. 277
278
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505
Figure 1. Scatter plots of respiratory AFs of benzene, toluene, and C8-aromatics versus BMI 506
and BFR, respectively. 507
508
509
510
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511
Figure 2. Regression analysis between respiratory AFs and exposure concentrations of 512
benzene (open squares), toluene (open cycles), and C8-aromatics (open triangles) collected 513
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Curve-fitting equations and their correlation coefficient (R2) and significance levels (p) were 515
also presented. R2 > 0.5 and p < 0.05 were used as critical values for significant correlations. 516
517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532
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For Table of Content Use Only 533
Decreased Human Respiratory Absorption Factors of Aromatic Hydrocarbons 534
at Lower Exposure Levels: The Dual Effect in Reducing Ambient Air Toxics 535
Zhong-Hui Huang,†,‡
Yan-Li Zhang,†,§
Qiong Yan,‖
Zhao-Yi Wang,†,‡
Zhou 536 Zhang,
† and Xin-Ming Wang*,†,§
537 538
539 540
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