The perpetuation of the misconception that rats receive a 3–5 times lower lung tissue dose than humans at the same ozone concentration

Figures & data

Figure 1. O₃ concentration-response from animal studies – the dose makes the poison. O₃ concentration (in ppb) versus severity of response Depuydt et al., 1999; Dye et al., 1999; Mittler et al., 1956; Scheel et al., 1959; Schelegle et al., 2001; Stokinger, 1957.

Figure 2. Database search results.

Table 1. Dose-related quotes from papers referencing Hatch et al. (1994).

Ozone studies	Dose-related	Correct	Incorrect	Uncertain
Pryor et al. (1996) (p. 155)	“However, the effect of O3 exposures in resting rats underestimate those observed in exercising human”.	✓
Zhao et al. (1998) (p. L45)	“In as much as rodents are less sensitive to O3 than humans by a factor of four to five, 0.6 ppm may reflect a human response at 0.12–0.15 ppm, a concentration comparable to the NAAQS”.		✘
Elder et al. (2000) (p. 229)	“The exposure concentration of O3 1 ppm is high, but is similar to an exposure to 0.25 ppm in exercising humans (Hatch et al., 1994) and was chosen to mimic high episodic concentrations in urban air …”.			?
Huffman et al. (2001) (p. 24)	“In addition, the biologic effects of a short-term exposure to 2 ppm O3 in rats appear to be relatively equivalent to exposure of 0.4 ppm O3 in exercising human subjects”.	✓
Kleeberger et al. (2001) (p. 719)	“It is important to note that actual delivered dose of O3 to the lung of rodents may be considerably less than may be expected by concentration × time considerations in human subjects, because rodents are obligate nose breathers”. AND “Support for the enhanced scrubbing efficiency of upper airways of rodents compared with humans come from Hatch et al. (1994)”.		✘
van Bree et al. (2001) (p. 704)	“Interspecies comparisons for the modeled or measured delivered O3 tissue dose in the respiratory tract indicate (1) that total uptake efficiency in rats is larger than in humans, (2) that there is a similarity between rats and humans for the D-R pattern for both acute inflammation and chronic alveolar interstitial thickness and (3) that humans may be more responsive than rats. (Hatch, 1994;…) These findings indicate that rats may be considered as a sensitive human model for O3 toxicity and that effects observed in rats may very well occur in humans, even at lower O3 levels (Hatch, 1994;…)”.		✘
Kumarathasan et al. (2002) (p. 196)	“The dose of ozone in the lung parenchyma of resting rats is about four to five times lower than the dose in the parenchyma of an exercising human subject”. “In other words, the ozone mass transfer rate in the lung parenchyma of our animals should approach realistically the ozone mass transfer rate in a human lung in a scenario of high environmental exposure such as jogging during an episode of severe air pollution”.	✓
Soulage et al. (2004) (p. 983)	“The effects observed in exercising humans are very similar to that produced in rat exposed at rest to a five-fold higher O3 concentration“.			?
Thomson et al. (2004) (p. 80)	“…the known interspecies differences in sensitivity to air pollutants (with humans being more responsive than rats …)”.		✘
Nadadur et al. (2005) (pp. 1719–1720)	“…, we have shown that the impact of acute exposure to O3 at 0.4 ppm with intermittent heavy exercise in humans resulted in lung tissue dosimetry approximately equal to that of the rat exposed sedentary to 2 ppm for the same 2-hr period”.	✓
Tsujino et al. (2005) (p. 483)	“For instance, Hatch et al. (1994) reported lower concentrations of O^18-labeled O3 in BAL constituents of a rat than those of a human following inhalation of the same concentration”.		✘
Huffman et al. (2006) (p. 125)	“Thus the dose used in this study is a biologically relevant human ozone dose”.		✘
Cho et al. (2007) (p. 830)	“…dosimetry studies in which rodents require 4 to 5 fold higher doses of O3 than humans to create an equal deposition and pulmonary inflammatory response”.		✘
Costa (2008a) (Book Ch. 28)(p. 1144)	“It is important to consider the role of exercise in a study of O3 or any inhalant before making cross-study comparisons, especially if that comparison is across species”.	✓
Wagner et al. (2007) (p. 1177)	"Pulmonary O3 dosimetry studies demonstrate that humans have 4–5 times greater pulmonary deposition of inhaled O3 than Fisher F344 rats. Furthermore, the Brown Norway rat is much less sensitive to O3 than F344 rats. As such, 1 ppm O3 in BN rats provides a reasonable exposure scenario to what might occur in humans”.		✘
Costa (2008b) (p. 108)	“…while the rats were exposed only at rest to the same O3 concentration or that concentration estimated to equate the total inhaled under exercise-induced ventilation. Reported that authors found that dose to the cells was similar between the human and rat only if the exposure concentration to the rat were increased by a factor of 5. Hence a simple use of exposure concentration would distort comparability of dose and effect”.	✓
Crémillieux et al. (2008) (p. 776)	“Based on comparative dose-effect studies in humans and rats, 0.5 ppm O3 exposure in rats can be extrapolated in to 0.1 ppm (200 μg/m^3) O3 concentration exposure in human”.		✘
Boussouar et al. (2009) (p. 76)	“Although this level of O3 is about 2X as high as that measured in polluted urban areas, the rat respiratory system is less sensitive to O3 than that of humans and a concentration of at least 0.5 ppm is required to mimic the pathological effects on the human lung”.		✘
Haque et al. (2009) (p. 2)	“In general, experimental animals require significantly higher doses of O3 exposure than humans to reach comparable amounts of O3 concentration in the distal lung”. AND "Therefore, it is necessary that rodents be exposed to high O3 concentration to better enable extrapolation of findings from animal studies to human”.		✘
Perpu et al. (2010) (pp. 62–63)	“Interspecies comparisons of O3 exposure have led to the following: (1) the total uptake efficiency in rats is larger than in humans; (2) there is a similarity b/w rodents and human for the D-R pattern for both acute inflammation and chronic alveolar interstitial thickness; (3) humans may be more responsive than rodents. These findings indicate that rodents may be considered as a sensitive human model for O3 toxicity and that effects observed in rodents may very well occur in humans, even at lower O3 levels”.		✘
Gackière et al. (2011) (p. 962)	In reference to using 0.5 and 2 ppm: " …this choice was justified when considering that O3 toxicity in resting rats is known to underestimate effects in exercising humans. Moreover, our primary goal was not to mimic air pollution peaks, but rather to provide fundamental data to describe the neural pathways activated by O3"	✓
Shore et al. (2011) (p. 7)	“…concentration is higher than the ambient O3 concentrations that would be observed even in the most polluted cities…; because rodents are much less susceptible to O3 than humans …; rodents require much higher concentrations of O3 to achieve the same O3 dose as humans…"		✘
Barreno et al. (2013) (pp. L126–L127)	“As the dose of O3 delivered to the lungs is the product of O3 concentration, exposure time, and minute ventilation (VE), exercising during exposure increases the VE of these subjects and, subsequently, the total dose of O3 delivered to their lungs”.	✓
Cho et al. (2013) (pp. 6 and 10)	“…results from dosimetry studies in which rodents require 4–5-fold higher doses of O3 than humans to create an equal deposition and pulmonary inflammatory response, either level of O3 used in the current study is a reasonable exposure level which is comparable with human exposures”.		✘
Hatch et al. (2013) (p. 63)	“Results confirm the use of VE as a factor in the extrapolation of inhaled dose of O3 at different levels of physical activity, and suggest that higher and more continuous activity levels will yield significant effects at even lower ambient levels of O3”.	✓
Martinez-Lazcano et al. (2013) (p. 346)	“Hatch et al. (1994) demonstrated that rodents require much higher doses compared with the exposure doses reported in humans in which neurological disorders due to O3 exposure were observed…”		✘
Oakes et al. (2013) (p. 31)	“Although our study used a high concentration of O3, exposure to 2 ppm O3 is comparable to 0.2 ppm O3 in a susceptible human subject”		✘
González-Guevara et al. (2014) (p. 1091)	“In animal models, the O3 is usually administered in high doses, i.e. the rats need be exposed to 2.0 ppm O3 in order to achieve immunological changes in the bronchoalveolar lavage fluid (BALF) as those found in human exposed to 0.4 ppm (Hatch et al., 1994)”		✘
Mikerov et al. (2014) (p. 334)	“The rationale for this dose is based on a study by Hatch et al. (1994) in which they reported that experimental animals required higher O3 concentrations than human to deliver comparable amounts of O3 to the distal lung”.		✘
Dye et al. (2015) (p. 23)	“First, the concentrations of O3 used were higher than ambient levels in most metropolitan areas. However, previous investigations have shown that obligate nasal-breathing, diurnally exposed, non-exercising rats require ≥5-fold higher O3 concentrations in order to achieve comparative O3 lung deposition (and oxidant-induced lung effects) compared with mouth-breathing humans undergoing intermittent exercise during experimental O3 exposure”.	✓
Miller et al. (2015) (p. 78)	“The 1 ppm O3 concentration used in this study for most analysis is considered high compared to human relevant dose. However, it has been shown that rats require 3–4Xs the concentration of O3 to acquire an equivalent dose to humans (Hatch, 1994). Thus, the concentrations of O3 used in our study, although higher than ambient levels, are appropriate for rat exposure”.		✘
Vella et al. (2015) (p. 1021)	“As a consequence, the toxicity of O3 observed for a given concentration in rats strongly underestimates the effect observed for the same concentration in humans, and thus, the effects observed in human are comparable to those produced in rats exposed to a five-fold higher O3 concentration”.		✘
Ward et al. (2015) (p. 85)	“Since exercise might increase lung deposition in humans inhaling 0.4 ppm O3 (Hatch et al., 2013), and it has been predicted that humans retain higher dose of O3 upon inhalation than rodents (Hatch et al., 1994), we believed that the concentration of 1.0 ppm in the present study was suitable for examining gene expression profiling”.		✘
Yang et al. (2015) (p. 572)	“That a 3-ppm inhaled dose in rodents results in O3 concentration in the lungs relevant to human exposure levels has been experimentally also validated by other by using oxygen-18-labeled O3. For example, in a study by Hatch et al., it was demonstrated that exposure to ^18O3 (0.4 ppm for 2 hours) caused 4- to 5-fold higher ^18O3 concentrations in human subjects than in rats. Rats exposed to 2.0 ppm had still less ^18O3 in BALF than human subjects exposed to 0.4 ppm”.		✘
Miller et al. (2016) (p. 314)	”It has been shown that in rats once inhaled, O3 deposition in the lung is 3–4 times less that what humans will experience (Hatch et al., 1994)”.		✘
Ong et al. (2015) (p. 332)	“For example, it takes approximately 4 to 5 times the concentration of O3 to induce pulmonary inflammation in rodents equivalent to that documented in exercising human subjects under similar controlled exposure conditions”.	✓
Snow et al. (2016) (p. 320)	"It is also known that the dose encountered in clinical studies involving intermittent exercise during a 0.2–0.4 ppm O3 exposure in humans results in a dose that is 3–4 times that experienced by non-exercising rodents (Hatch et al., 1994, 2013), indicating that although our high dose is not necessarily environmentally relevant, it is appropriate for examining O3-induced toxicity in a rodent model”.	✓
Stiegel et al. (2016) (p. 16)	“…used a high concentration of O3" AND "exposure to 2 ppm of O3 in a rodent was shown to be comparable to 0.2 ppm of O3 in a susceptible human subject”.		✘
Zhong et al. (2016) (p. 384)	“It has been experimentally documented that it takes approximately 4 to 5 times the concentration of O3 to induce pulmonary inflammation in laboratory rodents that is similar to that in exercising human subjects under similar controlled acute exposure conditions (Hatch et al., 1994, 2013). The airborne concentration that was chosen for this exposure was equivalent to an exercising human exposure of 0.15 ppm or approximately twice the concentration of the current U.S. National Ambient Air Quality Standard (NAAQS) for O3 (0.070 ppm)”.	✓

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