Impact of the hypothermic response in inhalation toxicology studies.
Previous studies from this laboratory showed that the decreases in Tco and associated functional parameters often observed in rodents following exposure to xenobiotic agents are capable of modulating the subsequent toxic response and that the magnitude of this induced hypothermic response may itself be modified by a number of experimental conditions. A moderate hypothermic response, characterized by a temperature drop of approximately 2 degrees C, appears to afford the optimal protection. Studies in which exposures occur through inhalation of harmful gases or particles present a special set of problems. In such studies, the dose of the toxic agent to which the animal is exposed is a function of the concentration of the agent in the atmosphere and the minute ventilation of the animal. Although ambient concentrations is generally held constant in laboratory studies, minute ventilation varies directly with metabolism, and both of these parameters may change significantly across experimental conditions. Thus, at low Tas, metabolism and minute ventilation are relatively high and uptake of inhalable toxic agents is increased. However, the development of the hypothermic response during the exposure entails a directly correlated reduction in these parameters and, presumably, in dose. For the most part, inhalation toxicological studies are conducted using resting animals or exercising humans. Animals are sometimes concurrently exposed to CO2 to simulate the increased ventilation of exercise and more closely mimic human studies. The experimental protocols employed in the above inhalation studies permitted examination of (1) the impact of species, size, handling stress, and changes in Ta on both the induced hypothermic response and the concomitant pulmonary toxicity; (2) the additive impact of exercise stress on O3 toxicity; and (3) the toxicity of ambient-derived particulate matter in normal rats and in rats with preexisting pulmonary inflammation. The results of these studies demonstrate that the magnitude of the induced hypothermic response is directly proportional to the uptake of the toxic agent by the lung and inversely proportional to the mass of the animal and the ambient temperature at which the exposure is conducted. The hypothermic response is sensitive to a number of experimental stresses including handling and changes in cage conditions. Exercise attenuates the hypothermic response, whereas CO2-stimulated increases in ventilation employed as an exercise surrogate may potentiate the response. Toxic exposures conducted in animals with lung disease or compromised pulmonary function may induce a severe hypothermic response while comparable exposures in normal animals produce only mild or moderate responses. In general, the development of the hypothermic response in the presence of ambient pollutants serves to decrease the minute ventilation of the animal and therefore limits the uptake and dose of the airborne toxicant. The results of these inhalation studies support our previous conclusions concerning the impact of the hypothermic response on toxicity and emphasize the need to monitor and incorporate these changes in functional parameters into analyses of toxicological data. Furthermore, because humans do not demonstrate a robust hypothermic response following exposure to toxic agents, extrapolation of the results obtained from animal studies and comparisons with data from human studies are considerably more complicated.
Watkinson
W P
WP
Pulmonary Toxicology Branch, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. watkinson@herl45.herl.epa.gov
Campen
M J
MJ
Lyon
J Y
JY
Highfill
J W
JW
Wiester
M J
MJ
Costa
D L
DL
D000280:Administration, Inhalation; D000818:Animals; D007035:Hypothermia / Q000139:chemically induced*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010126:Ozone / Q000633:toxicity; D005082:Physical Exertion; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D015262:Xenobiotics / Q000008:administration & dosage / Q000633:toxicity*
D015262:Xenobiotics; D010126:Ozone