PubMed · 3145433
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R A Crider, B A Rouse. 1988. Inhalant overview.. https://pubmed.ncbi.nlm.nih.gov/3145433/
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Rats were nose-only exposed for 6 h to polymeric methylenediphenyl-diisocyanate (pMDI). Concentrations varied from 0.12 to 12.7 mg/m(3) using a highly respirable aerosol. In regard to the concentration of the monomeric fraction of MDI contained in pMDI, the lowest concentration was in the range of the current workplace limit of MDI which is 0.05 mg/m(3). Biomarkers of exposure were determined in hydrolyzed urine (collection started after cessation of exposure for approximately 18 h; acid hydrolysis) and hydrolyzed hemoglobin (collection of blood approximately 20 h after cessation of exposure; alkaline hydrolysis). The determination revealed two-order of magnitudes higher yields of the biomarkers in urine when compared to hemoglobin. The concentration of analytes from the respective biological matrix was highly correlated with the airborne concentration of pMDI whilst their yields exhibited a reciprocal relationship to the airborne concentration of pMDI. A linear relationship could only be demonstrated by using a logarithmic transformation of data. With respect to the amount of 4,4'-methylenediphenyldianiline creatinine (MDA/g creatinine) in hydrolyzed urine of rats at an exposure level similar to the current workplace concentration of MDI, this marker of exposure was approximately 10-times lower in rats than predicted for humans. This suggests that the extrapolation of animal data to man as well as from one exposure regimen to another, without taking into consideration the different deposition/retention patterns of vapors (<or=0.05 mg/m(3)) or aerosols of MDI, might be error prone. In summary, taking into account previous and current experimental evidence, these data substantiate further that the formation of MDI-related biomarkers appear to be governed by spontaneously occurring, scavenging reactions at the portal-of-entry. Comparison of MDI with its corresponding amine support that the analytes determined stem from conjugated MDI rather than in vivo hydrolyzed MDI.
The toxicity of inhalatory exposure to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study physiologically based toxicokinetic (PBTK) modelling has been used to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of the model solvent toluene in rats. After construction of the model with parameters from literature, toxicokinetic data were collected from rats exposed to either a constant concentration or fluctuating concentrations at total external dose levels of 20,000 and 10,000 ppm x h for model validation. At the same exposure conditions the effects on learned performance were evaluated in separate groups of rats using a visual discrimination task. In general, the PBTK model provided reliable predictions of the toxicokinetics of toluene at different exposure scenarios, but it also tended to underestimate the blood and brain concentrations in the descending parts of the tissue concentration-time curves. At these high dose levels the differences in toxicokinetics between the constant and the fluctuating exposure groups were relatively small. The visual discrimination experiments demonstrated a slowing of response speed and disinhibition of responding in all toluene-exposed groups. The results suggest that the brain concentration of toluene is one of the major determinants of its effect on disinhibition of responding.
Styrene (ST) occurs ubiquitously in the environment and it is an important industrial chemical. After its uptake by the exposed mammalian organism, ST is oxidized to styrene-7,8-oxide (SO) by cytochrome P450 dependent monooxygenases. This reactive intermediate is further metabolized by epoxide hydrolase (EH) and glutathione S-transferase (GST). In long-term animal studies, ST induced lung tumors in mice but not in rats. Considering the lung to be the relevant target organ for ST induced carcinogenicity in mice, we extended a previously developed physiological toxicokinetic model in order to simulate the lung burden with ST and SO in the ST exposed mouse, rat and human. The new model describes oral and pulmonary uptake of ST, its distribution into various tissues, its exhalation and its metabolism to SO in lung and liver. It also simulates the distribution of the produced SO into the tissues and its EH and GST mediated metabolism in liver and in lung. In both organs the ST induced GSH consumption is described together with the formation of adducts to hemoglobin and to DNA of lymphocytes in ST exposed mice, rats and humans. The model includes compartments for arterial, venous and pulmonary blood, liver, muscle, fat, richly perfused tissues and lung. The latter organ is represented by two compartments, namely by the conducting and the alveolar zone. The physiological description of the pulmonary compartments relies on measured alveolar retentions, literature values of surface area of capillary endothelium, of the thickness of the tissue 'air-to-plasma', of the partition coefficient lung:blood and of metabolic parameters of ST and SO measured in pulmonary cell fractions of rodents and humans. Simulations of average pulmonary GSH levels in ST exposed rodents agree with measured data. The model predicts a significant GSH depletion (40%) in the conducting zone of mice exposed for 6 h to a ST concentration of only 20 ppm. In the conducting zone of rats, exposure to 200 ppm ST results in a loss of GSH of about 15% only. In humans, a pulmonary GSH reduction does not occur. The highest average pulmonary SO concentrations are predicted for mice, somewhat lower values for rats and by far the lowest ones for humans. Following steady state exposure to 20 ppm ST, the average SO concentration in mouse lungs is expected to be only three times higher than in rats. This difference diminishes to a factor of less than two at 70 ppm. In humans exposed to 20 ppm ST for 8 h, the average pulmonary SO burden of 0.016 micromol/kg is predicted to be about 17 and 50 times smaller than the corresponding values for rat and mouse. In agreement with reported values, pulmonary DNA adduct levels in rodents exposed to 160 ppm ST were simulated to be similar in rats and mice. In summary, there was no dramatic difference in the calculated average pulmonary SO burden between both animal species. However, pulmonary GSH loss was by far more expressed in ST exposed mice than rats. Since the model was validated on all available ST/SO data in mice, rats and humans, we consider it to be useful for estimating the risk resulting from exposure to ST.