Article pubs.acs.org/est
Human Exposure and Elimination Kinetics of Chlorinated Polyfluoroalkyl Ether Sulfonic Acids (Cl-PFESAs) Yali Shi,† Robin Vestergren,‡ Lin Xu,† Zhen Zhou,§ Chuangxiu Li,† Yong Liang,§,⊥ and Yaqi Cai*,†,⊥ †
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China ‡ Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, Stockholm SE 10691, Sweden § Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education, School of Chemical and Environmental Engineering, Jianghan University, Wuhan 430056, China ⊥ Institute of Environment and Health, Jianghan University, Wuhan 430056, China S Supporting Information *
ABSTRACT: The incomplete mass-balance of organic fluorine in human serum indicates the existence of unknown per- and polyfluoroalkyl substances (PFASs) with persistent and bioaccumulative properties. Here we characterized human exposure and elimination kinetics of chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs) in metal plating workers (n = 19), high fish consumers (n = 45), and background controls (n = 8). Cl-PFESAs were detected in >98% of the sampled individuals with serum concentrations ranging 6 years of employment the total elimination half-life (days) was calculated according to the following equation: t1/2, tot =
Cserum × 0.693 × Vd I
Figure 1. Box-whisker plot of the Cl-PFESA serum concentrations in background control (BC), high fish consumers (FC) and metal plating workers (MW). The horizontal line in the box represents the median value and the low and upper edge of the box mark the 25th and 75th percentiles. The whiskers extending from the box represent the maximum and minimum values excluding outliers.
where I (ng/kg/day) is the body weight normalized intake rate of chemical. The dietary intake was calculated as a weighted arithmetic mean concentration of the five sampled fish species which was multiplied with the average fish consumption (93 g/ day) and divided by the average body weight determined from questionnaires (see Table S3). The range of measured serum concentrations was used to estimate inter-individual variability in elimination half-lives. Statistical Evaluation. Statistical analyses were executed using the IBM PASW statistics 18.0 software (SPSS Inc., 1993− 2007) with a statistical significance threshold of p < 0.05. Summary statistics were calculated for analytes with detection frequencies >50% in serum/whole blood, urine, and fish samples. Concentrations below MLQ were assigned to be MLQ/2 in the statistical analysis. Spearman’s rho values were calculated for correlations. Mann−Whitney U-test and Kruskal−Wallis rank sum test was used to test differences in concentrations and ratios between different exposure groups.
Statistically significantly higher median concentrations of C8 and C10 Cl-PFESAs were observed in high fish consumers (93.7 and 1.60 ng/mL) and metal plating workers (51.5 and 1.60 ng/mL) compared to the background control group (4.78 and 0.08 ng/mL) (Kruskal−Wallis rank sum test, p < 0.01), whereas no statistically significant difference was observed between metal plating workers and high fish consumers (Kruskal−Wallis rank sum test, p > 0.402). C8 Cl-PFESA was detected in 74% of all urine samples ranging from 0.003 to 2.86 ng/mL. Contrastingly, C10 Cl-PFESA was only detected in two of the most highly exposed metal plating workers at 0.002 and 0.038 ng/mL, respectively. The concentrations of C8 Cl-PFESA and PFOS in urine and serum from the same individuals were strongly correlated (Spearman’s rho >0.827, p < 0.01, Table S5), suggesting that measurements in urine provide a good measure of the body burden of these two substances. C8 and C10 Cl-PFESAs were present in all fish muscle samples (Table S6) from Tangxun Lake whereas the C12 homologue was consistently below MLQ (0.065 ng/g ww). Median concentrations of C8 and C10 Cl-PFESAs ranged 0.770 to 2.17 ng/g and 0.052 to 0.099 ng/g, respectively, in the different fish species. Characterization of Exposure Pathways for Cl-PFESAs. The high detection frequency of C8 and C10 Cl-PFESAs at similar levels in background exposed individuals indicates that this class of contaminants may be ubiquitously present in the Chinese population. Although little is known about the
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RESULTS AND DISCUSSION Concentrations of Cl-PFESAs in Human Specimens and Fish Samples. The matrix spike-recoveries for whole blood, muscle, and urine were in the range 80.3−92.8%, 78.5− 104%, and 73.1−118% (see also Table S2). Reanalysis of linear PFOS in the sample extracts provided excellent agreement (r2 > 0.984) with previously reported values,32 demonstrating that storage did not have an effect on the quantified concentrations (Figure S7). For the 19 metal plating workers, concentrations in whole blood were transformed to serum equivalents using the correction factor of 0.5 that has previously been estimated for PFOS.38 Although the distribution between whole blood and serum has not been specifically studied for Cl-PFESAs, this D
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reflects a less efficient respiratory or gastrointestinal uptake of the C10 homologue. Alternative explanations could also be (i) a faster elimination of C10 compared to C8 Cl-PFESA or (ii) a different distribution between serum and other body compartments. The relative importance of these explanations related to the biological handling of C8 and C10 Cl-PFESA is further discussed in the section on elimination kinetics. Although a significantly elevated exposure was observed for high fish consumers and metal plating workers compared to the background control group, a large interindividual variability in Cl-PFESA concentrations (ranging 2−3 orders of magnitude) was also observed within the high exposure groups. For metal plating workers, statistically significantly lower median values were observed in individuals with 1 year of employment (1347 ng/mL) (Figure S8 and Table S8). For chemicals with relatively long elimination half-lives, serum concentrations are expected to increase as a function of exposure duration until a steady-state is reached after an extended period of constant exposure.32,44 The higher serum concentrations in metal plating workers with >1 years of exposure may, therefore, reflect a slow elimination rate in humans.32,44 However, additional factors related to the magnitude of occupational exposure (e.g., different work tasks, use of personal protection equipment) or individual variability in elimination rates may also be important to explain the individual variation in serum concentrations. The high fish consumer group was divided into five different subgroups, namely family members, > 0−1 years, > 1−3 years, > 3−6 years, and >6 years of employment at the fishery. Although the lowest concentrations of both C8 and C10 Cl-PFESAs were observed in the group with >0−1 years of employment, there were no statistically significant differences in median values of the different employment groups (Figure S8 and Table S8). The lack of a clear trend between Cl-PFESAs in serum and length of employment at the fishery may be explained by the fact that many individuals in this group reported a high fish consumption prior to starting their job at the fishery. Since the fish from Tangxun Lake was found to contain similar or lower concentrations of Cl-PFESAs compared to other parts of China,30 it is possible the majority of fishery employees have had a similar dietary exposure for a long time. Thus, the lack of a clear trend with duration of exposure indicates that the serum concentrations in fishery employees with >1 years of employment may be close to a steady-state. Contribution of Cl-PFESAs to the Sum of Known PFASs. In addition to Cl-PFESAs, a wide range of PFSAs and PFCAs were detected in serum and whole blood samples (Table S4). As reported previously by Zhou et al., highly elevated concentrations of PFOS (median 7840 ng/g) were observed in fish consumers from Tangxun Lake compared to the control group (median 17.4 ng/g).32 Elevated, but highly variable concentrations of PFOS (median 40.0 ng/mL; range 2.40−1323 ng/mL) were also observed in metal plating workers which probably reflects the parallel use of both F53B and perfluorooctane sulfonyl fluoride (POSF)-based commercial products. In Figure 2, the median composition profiles of identified organic fluorine attributed to ∑ClPFESAs, ∑PFSAs, and ∑PFCAs are presented for background controls, high fish consumers and metal plating workers, respectively. The highest contribution of Cl-PFESAs was observed in metal plating workers (41.3%) followed by the background control group (13.9%) and lowest contribution was
occurrence of Cl-PFESAs, the exposure of the background population is probably occurring through several exposure pathways (e.g., dietary intake, drinking water and dust ingestion). At the same time, the 20-fold higher median concentration of C8 Cl-PFESA in high fish consumers compared to background controls demonstrates that fresh water fish may be a particularly important vector of human exposure. This is a sensible finding given that fish consumption has been identified as a main predictor of human exposure to long-chain PFSAs and PFCAs,39 which have a comparable bioaccumulation potential in aquatic food webs with C8 ClPFESA.30 For metal plating workers, the elevated serum concentrations were probably due to inhalation of airborne ClPFESAs. Since the chrome metal plating solutions containing F-53B typically have a pH close to zero, volatilization of the protonated species and subsequent inhalation is likely a major occupational exposure pathway.40 However, additional exposure pathways including ingestion of dust particles, hand-tomouth contact or dermal uptake could also contribute to the total exposure of Cl-PFESAs in the workplace environment.41 When comparing the exposure in high fish consumers and metal plating workers with the background control group it should be noted that serum concentrations were not adjusted for demographic factors such as age/birth cohort and gender which are known to be important predictors of human serum concentrations for other PFASs.42,43 More comprehensive biomonitoring studies from different regions of China are, therefore, needed to better understand the human exposure to PFESAs. When investigating the relationship between Cl-PFESA homologues in serum, strong correlations between C8 and C10 Cl-PFESAs were observed in high fish consumers (p < 0.01; Spearman’s rho =0.795) and metal plating workers (p < 0.01; Spearman’s rho =0.911), whereas no significant correlation was observed in the background control group (p = 0.736; Spearman’s rho =0.143). There were also strong correlations observed between Cl-PFESA and PFOS serum concentrations in the above three population groups (p ≤ 0.01; Spearman’s rho =0.602−0.823, Table S7). The strong correlations between Cl-PFESA homologues and PFOS can be interpreted as an indication that these substances have similar sources of exposure in the respective exposure groups and similar toxicokinetic properties. However, it should be pointed out that ratios of Cl-PFESAs varied between the exposure groups. A significantly higher median C8/C10 ratio was observed in high fish consumers (53.3) compared to metal plating workers (36.6) (Mann−Whitney U-test, p < 0.01). The difference in C8/C10 ratios between metal plating workers and high fish consumers likely reflects the difference between nearfield and far-field exposure pathways for these two groups. While metal plating workers are exposed directly to the commercial F-53B mixture, the higher C8/C10 Cl-PFESA ratio in high fish consumers compared to metal plating workers may be due to preferential accumulation of C8 Cl-PFESA in aquatic food chains and subsequently a different homologue pattern in the primary exposure media. Intriguingly, the C8/C10 ratio in serum of metal plating workers was substantially higher than in commercial F-53B products (12.9 ± 2.6).29 Since no samples of workplace exposure media (e.g., air and dust) were analyzed in this study, it is difficult to fully explain this observation. However, assuming that the external exposure to Cl-PFESAs reflects the homologue pattern of the commercial mixture it seems plausible that the comparatively high C8/C10 ratio E
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human samples from different parts of China are needed to properly test this hypothesis. Elimination Kinetics of Cl-PFESAs. Since previous studies in animal models47,48 and human populations35,49 have shown that the clearance of PFASs may be sex-dependent, we calculated summary statistics for males and females separately (Table S9). However, due to the limited number of females in this study (n = 14), which also displayed a low detection frequency of Cl-PFESAs in urine, we could not detect any statistically significant differences between sexes. Hence, we hereafter discuss the elimination kinetics for Cl-PFESAs without differentiating between males and females. The median renal clearance rate of C8 Cl-PFESA (0.0016 mL/kg/day) was approximately five times lower than that of PFOS (0.0074 mL/ kg/day) (Mann−Whitney U test, P < 0.001). A low detection frequency of C10 Cl-PFESA in urine samples precluded accurate determination of the renal clearance rates. However, the average of paired serum and urine samples from the two most highly exposed metal plating workers (0.0006 mL/kg/ day) indicates a similar or slower excretion rate compared to C8 Cl-PFESA. The apparent trend of decreasing renal clearance rates in the order PFOS > C8 Cl-PFESA ≥ C10 Cl-PFESA is in line with observations for other PFASs, for which a higher hydrophobicity generally leads to a slower renal elimination.32,35,50 Thus, it seems unlikely that the unexpectedly high C8/C10 Cl-PFESA ratios in serum, as discussed above, could be explained by differences in elimination kinetics. In order to estimate total elimination half-lives, we took advantage of the fact that (i) the intake rate of C8 Cl-PFESA could be determined for high fish consumers from measurements in fish muscle samples and average fish consumption rates (Table S3) and (ii) serum concentrations of fishery employees with >6 years of employment appeared to have reached steady-state. In Table 2, the total and renal elimination half-lives of C8 Cl-PFESA and PFOS from this study are presented together with previously reported values for PFOS. Median total elimination half-lives of C8 Cl-PFESA and PFOS were 15.3 and 6.7 years, respectively. The substantially longer renal and total-elimination half-life of C8 Cl-PFESA compared to PFOS suggests that this compound is the most biopersistent PFAS in humans reported to date.32,35,41,51 At the same time, the 20-fold difference between renal excretion and total elimination half-lives indicates that other routes of clearance than urine are important for C8 Cl-PFESA. A similar, but less pronounced, discrepancy between renal and total elimination half-lives has also been observed for PFOS in previous studies (Table 2). Given the high persistence of PFESAs27,28 it seems unlikely, but not impossible, that metabolism contributes to the
Figure 2. Contribution of ∑Cl-PFESAs, ∑PFSAs and ∑PFCAs to the total identified organic fluorine content (ng F/mL) in human serum samples from the background control group (BC), high fish consumers (FC), and metal plating workers (MW). The stacked bar chart represent median values.
observed in high fish consumers (0.923%). The relatively low contribution of Cl-PFESAs in high fish consumers was primarily a consequence of the high PFOS concentrations, which represented >74.9% of the ∑PFASs in these samples. The exposure to Cl-PFESAs relative to other known PFASs via fish consumption may, however, vary greatly between different regions of China.26,28,29,45 In our previous study, we observed comparable concentrations of C8 Cl-PFESA in fish samples from Tangxun Lake, Xiaoqing River and a Beijing fish market whereas the concentrations of PFOS varied substantially.30 Higher concentrations of Cl-PFESAs may generally be expected in the central eastern provinces of China with heavy metal plating industry28,29 compared to western and northeastern China, where there are few known point sources of ClPFESAs.26,30,46 Given this anticipated geographical variability in environmental concentrations of PFASs it may also be expected that high fish consumers in some provinces of China have a significantly higher proportion of Cl-PFESAs in their serum. Transforming the serum concentrations of Cl-PFESAs to organic fluorine equivalents resulted in median values of 2.78 and 54.9 ng F/mL for the background control group and high fish consumers, respectively. These values are comparable to or higher than the range of arithmetic mean values of unidentified organic fluorine 2−18.5 ng F/mL in human serum samples from five different cities in China by Yeung et al.18 Assuming that Cl-PFESAs are present at a similar concentration range in highly industrialized coastal provinces of China (as discussed above) inclusion of this emerging class of PFASs could help to close the mass-balance of the organic fluorine in human serum. However, additional biomonitoring studies combining compound-specific analysis with total organic fluorine analysis of
Table 2. Estimated Biological Half-Lives via All Routes of Excretion (Total Elimination) and Renal Clearance for C8 Cl-PFESA and PFOS in Years C8 Cl-PFESA total elimination
renal clearance
mean
median
min
18.5
15.3
10.1
445
280
7.1
PFOS max 56.4
4230
mean
median
min
7.7 5.4
6.7 4.6 5.5 4.9 81.9 6.6 25 44
3.0 2.4
46.7 6.7 34 22
4.5 3.1 1.5 6 F
max 19.1 21.7
696 11 182 2183
study population
reference
predominantly male (58 males/14 females) predominantly male (24 males/2 females) male female predominantly male (58 males/14 females) young females (50 years) predominantly male
this study ref 51 ref 53 ref 53 this study ref 35 ref 35 ref 41
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cumulative risk assessment based on read-across extrapolations58 may be a valid and useful approach for Cl-PFESAs.
discrepancy between renal clearance and total elimination halflives. A more probable explanation is that the diminished renal excretion, due to higher hydrophobicity27,29 and proteinophilicity, makes biliary excretion relatively more important. This explanation finds some support in observations of a greater biliary excretion of long-chain PFCAs in rodents.50,52 However, more research combining in vitro sorption experiments, in vivo animal dosing, and observational studies in humans is needed to understand the toxicokinetics of novel PFASs. The estimated elimination kinetics presented in Table 2 demonstrates that C8 Cl-PFESA has a very long half-life in humans and that renal excretion cannot explain the total clearance. Nevertheless, it should be noted that the accuracy of elimination half-lives is limited by the underlying assumptions of the one-compartment model. First, the steady-state assumption may be an oversimplification of the real exposure situation despite that prolonged exposure did not result in significantly higher serum concentrations for the high fish consumers. Second, the estimated total elimination half-lives rely on estimates of the daily intake via fish consumption and the uncertainty in the self-reported fish consumption rates will be propagated to half-life calculations. Third, the assumption that C8 Cl-PFESAs has the same volume of distribution as PFOS is based on the blood/tissue distribution ratios in fish in the absence of mammalian data.30 Despite these uncertainties, the general agreement in total elimination half-life values for PFOS (AM 7.7; range 3.0−19.1 years) with those reported by Olsen et al.51 (AM 5.4; range 2.4−21.0 years) provides some confidence to the approach. Implications for Human Exposure and Health Risk Assessment of PFAS Alternatives. This is the first study, to our knowledge, of an emerging class of PFASs present in human samples at similar concentrations as PFOA and PFOS. So far, the main explanation for the unidentified fraction of organic fluorine in humans has emphasized the importance of unknown commercial fluorosurfactants used in textile- or paper treatment and their reaction intermediates.18,54,55 One of the underlying reasons for the strong research focus on these substances is that they were the major commercial product branches for the POSF- and telomer-based chemistry in Europe and North America with production volumes of several thousand tons per year.26 The apparent ubiquitous distribution of Cl-PFESAs in China, however, illustrates that persistent and bioaccumulative PFASs with significantly lower production volumes (estimated to ∼30 tons/year for F-53B) can also cause significant human exposure on a regional scale. Given that chemicals with lower production volumes often require a less rigorous hazard- and risk assessment,56 the findings of ClPFESAs in humans may serve as an important example in the context of chemical regulation of PFAS alternatives. The presence of Cl-PFESAs in human serum also raises questions about the potential health risks related to this exposure. Since the only toxicity study on Cl-PFESAs so far is an acute dose study in Zebra fish, a traditional human health risk assessment of this compound is not possible. Nevertheless, the similarities between PFOS and C8 Cl-PFESA with respect to (i) LC50 values in Zebra fish28 (ii) tissue distribution in crucian carp30 and (iii) slow elimination kinetics in humans (this study) certainly indicate that the biological handling of these compounds shares some common characteristics. Studies on the toxicity of PFECAs further support that inclusion of ether bonds in the perfluoroalkyl chain does not seem to have an effect on the toxicological mode-of-action.57 Thus,
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.est.5b05849. Additional information regarding solvents and chemical reagents, the HPLC conditions and confirmation of the Cl-PFESA standard, detail experimental conditions for HPLC and ESI-MS/MS and other materials are shown in Tables S1−S9 and Figures S1−S8 (PDF)
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AUTHOR INFORMATION
Corresponding Author
*Tel: +86 (10) 62849239; fax: +86 (10) 62849182; e-mail:
[email protected] (Y.C.). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was jointly supported by the National Natural Science Foundation of China (No. 21537004, 21377145, 21321004), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB14010201), the National Key Basic Research Program of China (2015CB931903), and the Swedish Research council FORMAS (No. 2014-514).
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