Acute toxicity when concentration varies with time: A case study with carbon monoxide inhalation by rats.
Exposure to time-varying concentrations of toxic compounds is the norm in both occupational settings and daily human life, but little has been done to investigate the impact of variations in concentration on toxic outcomes; this case study with carbon monoxide helps fill that gap. Median acute lethality of 10-, 20-, 40-, and 60-min continuous exposures of rats to carbon monoxide was well described by the toxic load model (k = C(n) × t; k is constant, C = test concentration, n = toxic load exponent, and t = exposure duration) with n = 1.74. Dose response-relationships for 1-h exposures including a recovery period between 10- or 20-min pulses showed greater similarity (in both median lethality and steepness of dose-response curve) to continuous exposures with equivalent pulse duration and concentration, rather than a 60-min exposure with equivalent time-weighted average concentrations or toxic load. When pulses were of unequal concentration (3:1 ratio), only the high concentration pulse contributed to lethality. These findings show that fluctuations or interruptions in exposure over a short time scale (60 min or less) can have a substantial impact on outcomes (when n > 1), and thus high-resolution monitoring data are needed to aid interpretation of resulting outcomes.
Naval Medical Research Unit Dayton (NAMRU-D), 2728 Q Street, Area B, Building 837, Wright-Patterson Air Force Base, OH 45433, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. Electronic address: lisa.sweeney.3.ctr@us.af.mil.
Lisa M
LM
Sweeney
Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010, USA.
Douglas R
DR
Sommerville
Naval Medical Research Unit Dayton (NAMRU-D), 2728 Q Street, Area B, Building 837, Wright-Patterson Air Force Base, OH 45433, USA; CAMRIS, Bethesda, MD, USA.
Michelle R
MR
Goodwin
Naval Medical Research Unit Dayton (NAMRU-D), 2728 Q Street, Area B, Building 837, Wright-Patterson Air Force Base, OH 45433, USA; CAMRIS, Bethesda, MD, USA.
R Arden
RA
James
Leidos, Linton, IN 47441, USA.
Stephen R
SR
Channel
D000818:Animals; D002248:Carbon Monoxide / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure / Q000009:adverse effects*; D007928:Lethal Dose 50; D008297:Male; D023421:Models, Animal; D008962:Models, Theoretical; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013997:Time Factors; D023382:Toxicity Tests, Acute / Q000379:methods*
D002248:Carbon Monoxide
Acute inhalation toxicity; Carbon monoxide; Dose-response models; Fluctuation; Toxic load model