Correspondence/Rebuttal Cite This: Environ. Sci. Technol. XXXX, XXX, XXX−XXX
pubs.acs.org/est
Comment on “Differential Health Effects of Constant and Intermittent Exposure to Formaldehyde in Mice: Implications for Building Ventilation Strategies”
Z
profoundly why Zhang et al. have not compared and discussed their results with effects reported in other exposure studies. Zhang et al. (2018) also report an increase of oxidative stress from measure of biomarkers in the BAL fluid. However, this is indeed not surprising. Inflammation by itself can cause ROS formation. Furthermore, it is also anticipated, because 0.8 ppm formaldehyde exposure decreases the respiratory rate, and thus the respiratory ventilation, in mice about 20%, for example, ref 12. This allows rodents, but not humans, “to significantly reduce their exposure to inhaled sensory irritants”.13 The sensory irritation of formaldehyde in the upper airways of mice causes a reflex initiated bradypnea, which results inter alia in decrease of the metabolic rate, decrease of carbon dioxide production, and demand for oxygen. Other outcomes are lower body temperature, heart rate, and blood pressure. This may initiate hypoxia-induced stress reactions. However, these effects are not relevant for human risk assessment. In summary, the authors’ conclusion about recommendation of different ventilation strategies according to the formaldehyde effects reported in their study may be characterized as inconsistent and thus dubious.
hang et al. (2018) have exposed mice to constant and intermittent exposure of formaldehyde at 0.4 and 0.8 ppm, respectively, for 7, 14, and 28 days, to investigate the effects of constant versus intermittent exposure.1 We are highly surprised that the authors find significant histopathological and inflammatory responses in the lungs from analysis of the bronchoalveolar lavage (BAL) fluid. Formaldehyde is among the most comprehensively studied chemicals in the world. Its toxicity is extensively described in several reviews, for example, refs 2−4. Gaseous formaldehyde is considered to deposit in the nasal cavity nearly quantitatively and does not reach internal organs;2 this is, for example, in contrast to the nonpolar ozone with negligible water solubility. Extensive exposure studies of rodents and nonhuman primates to gaseous formaldehyde have caused nasal toxicity. For instance, Kerns et al. (1983) exposed 120 male and 120 female rats and mice 6 h/day, 5 days/week for 24 months up to 14.3 ppm formaldehyde; lesions were only observed in the nasal cavity and proximal trachea on the basis of histopathological examinations of all major tissues from each organ system.5 Rush et al. (1983) exposed monkeys, male and female rats, male and female hamsters for 22 h/day, 7 days/week for 26 weeks up to 2.95 ppm formaldehyde; the only significant sign of toxicity was hoarseness, congestion, and squamous cell metaplasia in turbinates of monkeys and rats at 2.95 ppm formaldehyde exposure.6 Swenbergs’ group has elegantly demonstrated in many studies that formaldehyde induces DNA and protein adducts are limited to the nasal cavity and not observed in the lungs in rats and nonhuman primates.7,8 Likewise, no significant lung effects have been observed in human exposure studies up to 3 ppm for 3 h in asthmatics.9 Thus, we are deeply concerned about the validity of the lung effects reported by Zhang et al. (2018). We are seeking for a plausible explanation to understand their outcome. The generation of aerosol-free gaseous formaldehyde can be tricky without a generation system using paraformaldehyde. We have not been able to identify the formaldehyde generator system mentioned as ref 32 (Procedia Engineering, Vol 121 (p. 1−2240), X. Sun, J. Pei, eds., Tianjin, 12−15 July 2015) in the paper by Zhang et al. Thus, we assume that their generator system is similar to that described in other publications from the same laboratory, where formaldehyde is generated from a 10% formalin solution by impinging.10 Such generation may result in aerosol formation, which may bypass the scrubbing effect of the nose and potentially cause lower airway inflammation. Further, authors’ results are in contrast to a repeated exposure study in mice exposed to ≥0.6 ppm aerosol-free gaseous formaldehyde, which did not show an increase of inflammatory markers in BAL fluid.11 Thus, we wonder if Zhang et al. can provide another plausible explanation for their results. Furthermore, we wonder © XXXX American Chemical Society
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Peder Wolkoff* Gunnar D. Nielsen AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Zhang, X.; Zhao, Y.; Song, J.; Yang, X.; Zhang, J.; Zhang, Y.; Li, R. Environ. Sci. Technol. 2018, 52, 1551. (2) World Health Organization. Selected Pollutants. WHO Indoor Air Quality Guidelines; WHO Regional Office for Europe: Copenhagen, 2010; p 1−454. (3) Nielsen, G. D.; Larsen, S. T.; Wolkoff, P. Arch. Toxicol. 2013, 87, 73−98. (4) Nielsen, G. D.; Wolkoff, P. Arch. Toxicol. 2017, 91, 35−61. (5) Kerns, W. D.; Pavkov, K. L.; Donofrio, D. J.; Gralla, E. J.; Swenberg, J. A. Cancer Res. 1983, 43, 4382−4392. (6) Rusch, G. M.; Clary, J. J.; Rinehart, W. E.; Bolte, H. F. Toxicol. Appl. Pharmacol. 1983, 68, 329−343. (7) Edrissi, B.; Taghizadeh, K.; Moeller, B. C.; Kracko, D.; DoyleEisele, M.; Swenberg, J. A.; Dedon, P. C. Chem. Res. Toxicol. 2013, 26, 1421−1423. (8) Yu, R.; Lai, Y.; Hartwell, H. J.; Moeller, B. C.; Doyle-Eisele, M.; Kracko, D.; Bodnar, W. M.; Starr, T. B.; Swenberg, J. A. Toxicol. Sci. 2015, 146, 170−182. (9) Sauder, L. R.; Green, D. J.; Chatman, M. D.; Kulle, T. J. Toxicol. Ind. Health 1987, 3, 569−578.
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DOI: 10.1021/acs.est.8b00313 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Environmental Science & Technology
Correspondence/Rebuttal
(10) Zhang, Y.; Liu, X.; McHale, C.; Li, R.; Zhang, L.; Wu, Y.; Ye, X.; Yang, X.; Ding, S. PLoS One 2013, 8 (9), e74974. (11) Wolkoff, P.; Clausen, P. A.; Larsen, S. T.; Hammer, M.; Nielsen, G. D. Toxicol. Lett. 2012, 209, 166−172. (12) Nielsen, G. D.; Hougaard, K. S.; Larsen, S. T.; Wolkoff, P.; Clausen, P. A.; Wilkins, C. K.; Alarie, Y. Hum. Exp. Toxicol. 1999, 18, 400−409. (13) OECD. OECD Guidance Document 39. Acute Inhalation Toxicity Testing, Version 1. Draft Guidance and Review Documents/ Monographs - OECD, 2017.
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DOI: 10.1021/acs.est.8b00313 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
