Research Program Area: Health & Exposure
When low concentrations of xenobiotic organic vapors are inhaled by people, As in the case of environmental releases, the potential risk is dependent upon the systemic uptake and metabolic fate. Uptake fractions for certain chemicals have previously been measured at relatively high concentrations, but have not generally been available for low concentrations approaching environmental trace levels. This project developed a methodology for assessing the potential inhalation uptake fractions and metabolic rate of chemical vapors at low concentration utilizing adult nose-breathing beagles as surrogates for people. Quantitative measurements were made 01' the systemic uptake during nasal breathing of very law concentrations in dry air of six selected chemical vapors: benzene, dimethylnitrosamine, chloroform, methyl bromide, trichloroethylene, and formaldehyde. Attempted measurements of the uptake of ethylene oxide were unsuccessful because of the rapid degradation of this reactive chemical. The experimental subjects were three adult female beagles obtained from the dog colony at UC Davis; each beagle was studied with each of the six vapors. The beagles suffered no harm or pain, and they were returned to the dog colony in good health at the end of the study. A special apparatus for the controlled inhalation exposure of individual beagles was designed, built and tested. It used a respirator demand-air breathing valve that separated inhaled and exhaled gases. The special method of concurrent flow spirometry was adapted to the system to measure the volumes of air inhaled and exhaled during the exposures and the breathing rate. Each individual unanesthetized dog was immobilized in foam rubber padding and fitted with a latex mask to prevent oral breathing. Each dog was comfortable and awake during the exposures and the spontaneous breathing was normal for the resting state. Each organic vapor was produced from high specific activity radioactive carbon-14-labeled chemicals at concentrations in the range from 1.4 ppb (formaldehyde) to 594 ppb (chloroform) and the assays of the materials were done using radioanalytical techniques. The concentrations of each chemical vapor under study were measured before and after inhalation to determine uptake efficiency. Exhaled air, blood, urine, and fecal samples were used to measure the metabolic pattern of blood concentration and excretion of each chemical or it's metabolites during and after exposure. The individual exposures were three hours long in 30 minute monitoring sub-periods and the metabolic behavior of the chemicals was followed for 117 hours after exposure. The steady state fractional systemic uptake of the total vapor was 39.5%±1 .0%SE for methyl bromide, 39.8%±1.5%SE for chloroform, 42.1%±2.2%SE for benzene 48.0$±0.8%SE for trichloroethylene, 53.6%±2.1%SE for dimethylnitrosamine, and 54.4%±0.9%SE for formaldehyde. These results indicate that inhalation uptake is primarily a ventilation process dependent upon pulmonary ventilation and the diffusitivities of the respective vapors in air within the lung. Similar resting uptake fractions are expected for people with somewhat lower uptake fractions with increased activity and breathing. After the three-hour exposure the 14C blood concentrations as percentage of total inhaled vapor were 1.6%±0.1% SE for methyl bromide 3.3%±0.6% SE for chloroform, 9.2%±5.4% SE for benzene, 2.5%±0.4% SE for trichloroethylene, 5.6%±0.4% SE for dimethylnitrosamine, and 12.4%±4.7% SE for formaldehyde. Clearance half-times after exposure based upon the radiocarbon label ranged from about ten hours or less for dimethylnitrosamine, chloroform, and formaldehyde to about 40 hours for methyl bromide. Previously reported uptake measurements for trichloroethylene and benzene by people at much higher concentrations (about 100 ppm) agreed within about 15% with the results of the uptake measurements in beagles for these two vapors at near environmental concentrations (about 100ppm). A previously reported study of the uptake of methyl bromide by rats measured uptake of 48%±2% SE at 1.6 ppm compared to 39.5%±1.0%SE for beagles at about 0.3 ppm. The results indicate that the respiratory uptake of the inhaled xenobiotic vapors at concentrations from about 0.1 ppm to about 100 ppm depended primarily on respiratory ventilation and vapor diffusivity with uptake primarily in the lung parenchyma. Similar uptake is therefore expected for all mammalian species under dynamically similar conditions, Increased or altered respiratory patterns are expected to alter uptake, such as reducing uptake fraction during exercise.
For questions regarding this research project, including available data and progress status, contact: Research Division staff at (916) 445-0753
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