Alan R. Dahl

Comparison of the disposition of butadiene epoxides in Sprague-Dawley rats and B6C3F1 mice following a single and repeated exposures to 1,3-butadiene via inhalation.

1,3-Butadiene (BD), a compound used extensively in the rubber industry, is a potent carcinogen in mice and a weak carcinogen in rats in chronic carcinogenicity bioassays. While many chemicals are known to alter their own metabolism after repeated exposures, the effect of exposure prior to BD on its in vivo metabolism has not been reported. The purpose of the present research was to examine the effect of repeated exposure to BD on tissue concentrations of two mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2). Concentrations of BD epoxides were compared in several tissues of rats and mice following a single exposure or ten repeated exposures to a target concentration of 62.5 ppm BD. Female Sprague-Dawley rats and female B6C3F1 mice were exposed to BD for 6 h or 6 h x 10 days. BDO and BDO2 were quantified in blood and several other tissues following preparation by cryogenic vacuum distillation and analysis by multidimensional gas chromatography-mass spectrometry. Blood and lung BDO concentrations did not differ significantly (P < or = 0.05) between the two exposure regimens in either species. Following multiple exposures to BD, BDO levels were 5- and 1.6-fold higher (P < or = 0.05) in mammary tissue and 2- and 1.4-fold higher in fat tissue of rats and mice, respectively, as compared with single exposures. BDO2 levels also increased in rat fat tissue following multiple exposures to BD. However, in mice, levels of this metabolite decreased by 15% in fat, by 28% in mammary tissue and by 34% in lung tissue following repeated exposures to BD. The finding that the mutagenic epoxide BDO, which is the precursor to the highly mutagenic BDO2, accumulates in rodent fat may be important in assessing the potential risk to humans from inhalation of BD.

Comparative Dosimetry of Inhaled Materials: Differences among Animal Species and Extrapolation to Man

*Lovelace Inhalation Toxicology Research Institute, P.O. Box 5890, Albuquerque. New Mexico 87185; t/nstitute 0/ Environmental Medicine. New York University Medical Center. 550 First Avenutr. New York. New York 10016; ~Chemicallndustry Institute a/Toxicology, Research Triangle Park, North Carolina 27709; and §National Institute Q[ Environmentaillealth Sciences, Research Triangle Park. NOrlh Carolina 27709

Dissolution of metal tritides in a simulated lung fluid

Metal tritides including titanium tritide (Ti 3Hx) and erbium tritide (Er 3Hx) have been used as components of neutron generators. The current understanding of metal tritides and their radiation dosimetry for internal exposure is very limited, and the ICRP Publication 30 does not provide for tritium dosimetry in metal tritide form. However, a few papers in the literature suggest that the solubility of metal tritides could be low. The current radiation protection guidelines for metal tritide particles are based on the assumption that their biological behavior is similar to tritiated water, which could be easily absorbed into body fluid. Therefore, these particles could have relatively short biological half-lives (10 d). If the solubility is low, the biological half-life of metal tritide particles and the dosimetry of an inhalation exposure to these particles could be quite different from tritiated water. This paper describes experiments on the dissolution rate of titanium tritide particles in a simulated lung fluid. Titanium tritide particles with mean sizes of 103 microm (coarse) and 0.95 microm (fine) were used. The results showed that the coarse particles dissolved much more slowly than the fine particles. The long-term dissolution half times were 361 and 33 d for the coarse and fine particles, respectively. Dissolution data of the fine particles were consistent with the diffusion theory. The dissolution half times were longer than the 10-d biological half time for tritiated water in the body. This finding has significant implications for the current health protection guidelines, including annual limits of intakes and derived air concentrations.

A RAPID COMBUSTION METHOD FOR THE ACCURATE DETERMINATION OF LOW LEVELS OF TRITIUM IN BIOLOGICAL SAMPLES

The authors have developed a simple, accurate method to combust low-level, tritium-containing tissue samples by modifying a tube furnace with two combustion zones. The sample is pyrolyzed upstream under a slow stream of argon, after which oxygen is added to the gas stream,and pyrolysis gases arecombusted over a platinum catalyst. The charred sample is combusted by changing the gas from argon to pure oxygen. A small volume of steam is then passed through the tube furnace to purge adsorbed tritiated water from the walls of the apparatus. The original design was changed in two ways. (1) Gas inlets were arranged so that baffles or porous plugs are not needed to maintain stable combustion. This change greatly reduces the residual radioactivity carried over from one sample to the next (typically 0.3 0.2 %). (2) Combustion gases are completely condensed in a cold trap with liquid nitrogen so that 100% of the tritium in the sample is trapped. The colorless, trapped water is directly dissolved in scintillation flu...

Clearance of Sulfuric Acid-Introduced 35S from the Respiratory Tracts of Rats, Guinea Pigs and Dogs Following Inhalation or Instillation

The clearance of sulfuric acid-introduced 35S from the upper and lower respiratory tracts of rats, guinea pigs and dogs was measured. Sulfuric acid was administered by instillation and by inhalation for each species. Clearance into the blood and gastrointestinal tract was measured along with determination of 35S remaining at the site of administration at sacrifice. Different rates of clearance from different sites within the dog lung were indicated with rates of clearance increasing with decreasing airway diameter. Half-times of clearance from all sites in the lung and for all species were from 2-9 min. There appeared to be some species differences, with clearance for dogs being slower than for guinea pigs, which was slower than for rats. Upper respiratory tract clearance was much slower than for lung and may not have been primarily by way of the blood. The data indicate that the clearance of sulfuric acid-introduced 35S in vivo is faster than previous studies in isolated perfused lungs had indicated. The results may be general for water soluble, ionized chemical species.

HPLC DETERMINATION OF TRITIATED POLYCYCLIC AROMATIC HYDROCARBON METABOLITES IN THE SUBFEMTOMOLE RANGE

In experiments to determine the toxicokinetics of polycyclic aromatic hydrocarbons (PAHs) in lungs at environmentally realistic levels, a technique to measure metabolites in tissueat subfemtomolar concentrations was needed. Postexposure blood concentrations of \[3H]benzo\[a]pyreneand\[3H]pyrenemetabolites were determined after intratracheal instillation of 10 ng in three beagle dogs. 3H20 was distilled from samples in vacuo, and the residual radioactivity was fractionated into water-soluble, bound (pellet-associated), and organic-extractable fractions. Radioactivity in the pellet and aqueous fraction was determined by complete combustion and subsequent liquid scintillation counting. The organicsoluble fractions, which contained the metabolites of interest, also contained lipids that were inseparable from the highly lipophilic PAHs. The lipids were saponified using CaO, extracted with ethyl acetate, resuspended in methanol, and fractionated using RP-HPLC. Metabolites were identified by coelution with authe...

Urinary butadiene diepoxide: a potential biomarker of blood diepoxide

The carcinogenicity of 1,3-butadiene (BD) varies greatly in the rodent species in which 2-year bioassay studies were completed. This raises the question of whether the risk of BD exposure in humans is more like that of the sensitive species, the mouse, or more like that of the resistant species, the rat. Numerous studies have indicated that one reason for the species differences in response to BD is that the blood and tissues of BD-exposed mice contain high levels of both the mono- and the diepoxide metabolite, while the tissue and blood of exposed rats contain very little of the diepoxide. The diepoxide is far more mutagenic than the monoepoxide, and so it is reasonable that the diepoxide plays a major role in tumor induction in the mouse. If the diepoxide is the primary carcinogen, the presence of the diepoxide in the blood of exposed individuals should be an indicator of risk from BD exposure. In this study, we report that the diepoxide is sufficiently stable to be excreted into the urine of exposed rodents and that the urinary levels of the diepoxide reflect the relative levels of the compound in the blood of the two species. The conclusion is that urinary diepoxide should be investigated as a potential biomarker of the formation of the diepoxide in humans exposed to BD.

Deposition of sulfuric acid mist in the respiratory tracts of guinea pigs and rats

Radiolabeled sulfuric acid mists in the size range of 0.4-1.2 micron mass median aerodynamic diameter (MMAD) were generated at 20 and 80% relative humidity at concentrations from 1.3 to 20 micrograms/l. Guinea pigs and rats were exposed to these aerosols by the nose-only route for short periods (30 s) and were quickly sacrificed and dissected. The regional respiratory-tract deposition patterns were measured. The results indicate that regional deposition fraction is positively correlated with droplet size of the sulfuric acid but is not correlated with atmospheric concentration or relative humidity over the ranges of the parameters studied. A comparison of the data obtained in these studies with those from earlier studies indicates that the deposition of sulfuric acid in the respiratory tract of rats is greater than for nonhygroscopic aerosols having similar MMADs. This may be due to the growth of the droplets in the high humidity of the respiratory tract.

Deposition of sulfuric acid mists in the respiratory tract of beagle dogs.

Beagle dogs were exposed to 35S-labeled sulfuric acid mists. The size range of the mist droplets was 0.4-1.1 micrometer mass median aerodynamic diameter (MMAD), and the external relative humidity was 20 or 80%. Immediate isolation of the respiratory tract and measurement of radioactivity in specified portions allowed determination of regional deposition. It was found that inhaled sulfuric acid mists in the size ranges studied had deposition patterns similar to those for dry aerosols. The effect of hygroscopicity for these aerosols was not dominant in determining the site of deposition.