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.

Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro-1,2,4-Triazol-5-One.

3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO.

Toxicokinetic Model Development for the Insensitive Munitions Component 2,4-Dinitroanisole.

The Armed Forces are developing new explosives that are less susceptible to unintentional detonation (insensitive munitions [IMX]). 2,4-Dinitroanisole (DNAN) is a component of IMX. Toxicokinetic data for DNAN are required to support interpretation of toxicology studies and refinement of dose estimates for human risk assessment. Male Sprague-Dawley rats were dosed by gavage (5, 20, or 80 mg DNAN/kg), and blood and tissue samples were analyzed to determine the levels of DNAN and its metabolite 2,4-dinitrophenol (DNP). These data and data from the literature were used to develop preliminary physiologically based pharmacokinetic (PBPK) models. The model simulations indicated saturable metabolism of DNAN in rats at higher tested doses. The PBPK model was extrapolated to estimate the toxicokinetics of DNAN and DNP in humans, allowing the estimation of human-equivalent no-effect levels of DNAN exposure from no-observed adverse effect levels determined in laboratory animals, which may guide the selection of exposure limits for DNAN.

Submarine exposure guideline recommendations for carbon dioxide based on the prenatal developmental effects of exposure in rats.

BACKGROUND: To protect crewmember health, the U.S. Navy sets exposure limits for more than 200 components of submarine atmospheres. The addition of females to nuclear submarines required a reevaluation of these exposure limits, originally established for all-male crews. In the case of carbon dioxide (CO2 ), the only available data suitable for deriving an exposure limit were from a 2010 study sponsored by the British Royal Navy that reported a debatable interpretation casting doubt on whether current U.S. Navy exposure limits served to protect fetal developmental health. METHODS: About 120 time-mated female Sprague-Dawley rats (Crl: CD[SD]) were exposed to CO2 at levels of 1.5%, 2.0%, 2.5%, and 3.0% from gestation days 6 to 20. Dams were euthanized and fetuses were examined. RESULTS: Findings with implications for exposure limits for CO2 during pregnancy were an increased mean litter proportion of early resorptions and a lower mean litter proportion of viable fetuses in the 3.0% CO2 group. CONCLUSION: The results yield a No Observed Adverse Effect Level (NOAEL) of 2.5% and a Lowest Observed Adverse Effect Level (LOAEL) of 3.0%. The results reasonably allow a point of departure of 2.5% CO2 for deriving an exposure recommendation. An interspecies uncertainty factor was applied to derive a recommended 90-day continuous exposure limit (CEL) of 0.8% for CO2 . As reproductive endpoints that are developmental in nature must be assumed to result from a single exposure at a critical point during gestation, it is further recommended that the 24-hr emergency exposure limit (EEL) also be 0.8%.