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PubMed2001

Assessing the reliability of PBPK models using data from methyl chloride-exposed, non-conjugating human subjects.

Physiologically based pharmacokinetic (PBPK) models are often optimized by adjusting metabolic parameters so as to fit experimental toxicokinetic data. The estimates of the metabolic parameters are then conditional on the assumed values for all other parameters. Meanwhile, the reliability of other parameters, or the structural model, is usually not questioned. Inhalation exposures with human volunteers in our laboratory show that non-conjugators lack metabolic capacity for methyl chloride entirely, and that elimination in these subjects takes place via exhalation only. Therefore, data from these methyl chloride exposures provide an excellent opportunity to assess the general reliability of standard inhalation PBPK models for humans. A hierarchical population PBPK model for methyl chloride was developed. The model was fit to the experimental data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. In a Bayesian analysis, it is possible to merge a priori knowledge of the physiological, anatomical and physicochemical parameters with the information embedded in the experimental toxicokinetic data obtained in vivo. The resulting estimates are both statistically and physiologically plausible. Model deviations suggest that a pulmonary sub-compartment may be needed in order to describe the inhalation and exhalation of volatile adequately. The results also indicate that there may be significant intra-individual variability in the model parameters. To our knowledge, this is the first time that the toxicokinetics of a non-metabolized chemical is used to assess population PBPK parameters. This approach holds promise for more elaborate experiments in order to assess the reliability of PBPK models in general.

Adult↗
PubMed1990

Benzene hemoglobin adducts in mice and rats: characterization of formation and physiological modeling.

Benzene is a myelotoxin and a human leukemogen. Humans are exposed to this compound, both occupationally and environmentally. This study was conducted to determine whether formation of benzene-derived adducts with blood hemoglobin (Hb) can be used as a biomarker of exposure to benzene. B6C3F1 mice and F344/N rats were given 0.1 to 10,000 mumol [14C]benzene/kg body wt, orally. Twenty-four hours later, animals were euthanized, and globin was isolated from blood samples. The globin was analyzed by liquid scintillation spectrometry for the presence of [14C]benzene-derived adducts. Hb adduct formation was linear with respect to dose for amounts of up to 500 mumol [14C]benzene/kg body wt, for both rodent species. Within this linear dose-response range, mice formed adducts from [14C]benzene approximately 3.5 times less efficiently [0.022 +/- 0.010 (pmol adducts/mg globin)/(mumol/kg body wt dose)] than did rats [0.076 +/- 0.014 (pmol adducts)/(mumol/kg body wt dose)]. Benzene-derived Hb adducts also accumulated linearly when mice and rats were given up to three daily doses of 500 mumol [14C]benzene/kg body wt. These data were used to develop a physiological model for benzene-derived Hb adduct formation. Both first-order and saturable pathways for adduct formation were incorporated. The results showed that the model simulated the levels of Hb adducts in both mice and rats after oral exposures to benzene and predicted the levels of Hb adducts present after inhalation exposure. These studies suggest that Hb adducts might be useful biomarkers for human exposures to benzene.

Animals↗
PubMed1992

Modulation of pulmonary immune defense mechanisms by sulfuric acid: effects on macrophage-derived tumor necrosis factor and superoxide.

There is considerable interest in the potential health effects resulting from inhalation of acidic aerosols. However, except for well documented irritant effects and acid-induced changes in lung clearance function, other potential health effects have not been well defined. This study was designed to provide further insight regarding the relationship of sulfuric acid aerosol to the pathogenesis of respiratory disease by describing the effects of inhaled acid on the release and/or activity of biologically active mediators critical for maintaining pulmonary immunocompetence and resistance against infectious diseases. Results of this study demonstrated that a single inhalation exposure of rabbits to environmentally relevant and higher concentrations of sulfuric acid depresses the release/activity of lipopolysaccharide-stimulated tumor necrosis factor-alpha and also reduces the ability of pulmonary macrophages to produce superoxide anion radical in response to opsonised zymosan. These findings should be considered when evaluating the health risks associated with sulfuric acid exposure.

Administration, Inhalation↗
PubMed2000

Characterization of an aerosol chamber for human exposures to endotoxin.

The objective of this study was to develop and characterize an exposure chamber in which human subjects could be exposed to low dust concentrations carrying an endotoxin coating. An exposure chamber, dust dispersion method, and endotoxin characterization technique were developed for inhalation exposures. A 6.27 m3 exposure chamber was designed and constructed from cinder block, glass windows, and Plexiglas. Using an acetone adhesion process, Enterobacter agglomerans were adsorbed onto respirable cellulose particles to create the endotoxin aerosol. The size distribution of the endotoxin-treated particles was verified using light microscopy and cascade impactors. A dry powder dust generator was refined to consistently disperse small quantities of the aerosol into the chamber to maintain dust concentrations at approximately 250 micrograms/m3. Dust levels during the chamber exposures were monitored using a portable continuous aerosol monitor (PCAM). During initial exposure runs, PCAM monitoring stations were positioned at different locations within a 0.5-meter matrix to document mixing patterns. Total dust and cascade impactor samples were collected throughout each exposure period to characterize the chamber operating system and insure the mean airborne dust concentration fulfilled target levels. A one-factor analysis of variance at the 95 percent confidence interval illustrated that there was not a statistically significant difference in the mean dust concentration throughout the exposure runs compared to the individual runs. Together the consistency of the total dust filters, endotoxin concentrations, and aerosol-monitoring instrument were adequate to allow use of the chamber for experimental studies involving human volunteers.

Aerosols↗
PubMed1977

Human exposure to tetrachloroethylene: inhalation and skin contact.

There is considerable potential for worker exposure to tetrachloroethylene, both by skin contact and by inhalation, during its use in dry cleaning and degreasing operations. This paper reviews accounts of both accidental overexposures of workers and controlled exposures of human subjects by these two routes of exposure. Several reported cases of accidental overexposure to anesthetic doses of the chemical reveal that recovery was generally complete but prolonged, and accompanied by many days of measurable levels of the chemical in the patient's alveolar breath. Chronic overexposures of workmen have lessened since the general acceptance by the Western world of the recommended TLV of 100 ppm for 8 hr of daily exposure. Controlled inhalation studies with volunteer subjects at this level of exposure revealed no effects upon health but did indicate a slight decrement in performance on a coordination test. Additional behavioral and neurological tests revealed no interactive effects when alcohol or diazepam, two depressant drugs, were added singly to tetrachloroethylene exposures. Individual susceptibility to the vapor of this chemical, as evidenced by subjective complaints, was noted in approximately one of ten subjects. The authors conclude that the TLV concentration of 100 ppm in the workplace has a negligible margin of safety regarding unimpaired performance during repeated exposures which could be especially hazardous if the worker is physically active or is in a situation where skin absorption presents an added burden.

Environmental Exposure↗
PubMed2005

Characterization of marine aerosol for assessment of human exposure to brevetoxins.

Red tides in the Gulf of Mexico are commonly formed by the fish-killing dinoflagellate Karenia brevis, which produces nine potent polyether brevetoxins (PbTxs). Brevetoxins can be transferred from water to air in wind-powered white-capped waves. Inhalation exposure to marine aerosol containing brevetoxins causes respiratory symptoms. We describe detailed characterization of aerosols during an epidemiologic study of occupational exposure to Florida red tide aerosol in terms of its concentration, toxin profile, and particle size distribution. This information is essential in understanding its source, assessing exposure to people, and estimating dose of inhaled aerosols. Environmental sampling confirmed the presence of brevetoxins in water and air during a red tide exposure period (September 2001) and lack of significant toxin levels in the water and air during an unexposed period (May 2002). Water samples collected during a red tide bloom in 2001 showed moderate-to-high concentrations of K. brevis cells and PbTxs. The daily mean PbTx concentration in water samples ranged from 8 to 28 microg/L from 7 to 11 September 2001; the daily mean PbTx concentration in air samples ranged from 1.3 to 27 ng/m(3). The daily aerosol concentration on the beach can be related to PbTx concentration in water, wind speed, and wind direction. Personal samples confirmed human exposure to red tide aerosols. The particle size distribution showed a mean aerodynamic diameter in the size range of 6-12 microm, with deposits mainly in the upper airways. The deposition pattern correlated with the observed increase of upper airway symptoms in healthy lifeguards during the exposure periods.

Aerosols↗
PubMed2005

Delta9-tetrahydrocannbinol accounts for the antinociceptive, hypothermic, and cataleptic effects of marijuana in mice.

Although it is widely accepted that delta9-tetrahydrocannabinol (delta9-THC) is the primary psychoactive constituent of marijuana, questions persist as to whether other components contribute to marijuana's pharmacological activity. The present experiments assessed the cannabinoid activity of marijuana smoke exposure in mice and tested the hypothesis that delta9-THC mediates these effects through a CB1 receptor mechanism of action. First, the effects of delta9-THC on analgesia, hypothermia, and catalepsy were compared with those of a marijuana extract with equated delta9-THC content after either i.v. administration or inhalation exposure. Second, mice were exposed to smoke of an ethanol-extracted placebo plant material or low-grade marijuana (with minimal delta9-THC but similar levels of other cannabinoids) that were impregnated with varying quantities of delta9-THC. To assess doses, delta9-THC levels in the blood and brains of drug-exposed mice were determined following both i.v. and inhalation routes of administration. Both marijuana and delta9-THC produced comparable levels of antinociception, hypothermia, and catalepsy regardless of the route of administration, and these effects were blocked by pretreatment with the CB1 antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl]. Importantly, the blood and brain levels of delta9-THC were similar in mice exhibiting similar pharmacological effects, regardless of the presence of non-delta9-THC marijuana constituents. The present experiments provide evidence that the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from delta9-THC content acting at CB1 receptors and that the non-delta9-THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.

Analgesics↗
PubMed1994

Lactational transfer of tetrachloroethylene in rats.

Tetrachloroethylene (PCE) is a commonly used organic solvent and a suspected human carcinogen, reportedly transferred to human breast milk following inhalation exposure. Transfer of PCE to milk may represent a threat to the nursing infant. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively assess the transfer of inhaled PCE into breast milk and the consequent exposure of the nursing infant. The model was validated in lactating rats. Lactating Sprague-Dawley female rats were exposed via inhalation to PCE at concentrations ranging from 20-1000 ppm, and then returned to their nursing, 10- to 11-day-old pups. Tetrachloroethylene concentrations in the air, blood, milk, and tissue were determined by gas chromatography and compared to model predictions. The model described the distribution of inhaled PCE in maternal blood and milk, as well as the nursed pup's gastrointestinal tract, blood, and tissue. Several computer simulations of PCE distribution kinetics in exhaled air, blood, and milk of exposed human subjects were run and compared with limited human data available from the literature. It is concluded that the PBPK model successfully described the concentration of PCE in both lactating rats and humans. Although predictions vs. observations were good, the model slightly underpredicted the peak whole pup PCE concentration and underpredicted systemic clearance of PCE from the pup.

Adipose Tissue↗
PubMedDate not supplied

A dynamic closed-loop recirculating inhalation chamber for conducting pharmacokinetic and short-term toxicity studies.

Tests for evaluating the hazard of inhalation exposure generally require large quantities of the chemical of interest. This paper describes an inhalation technique that involves a dynamic closed-loop recirculating system which uses only small amounts of toxicant since the test atmosphere to which the animals are exposed is recycled. Carbon dioxide and water are continually removed while the oxygen and test substance absorbed by the animals are replenished. The approach described is different from other closed-loop chambers since the test substance is continuously added to the chamber and the air concentration is continuously measured. The technique was successfully used to expose 20 adult rats for up to 12 consecutive hours to 100 ppm of 14C-carbon tetrachloride yet only 2-3 mL of test material were consumed. The inhalation chambers were fabricated from standard 40-liter cylindrical glass bell jars. A high number of air changes (35-40 equivalent chamber volumes per hour) permitted exposure of as many as five adult rats per 10 liters of chamber volume. This closed-loop approach should prove to be especially useful for evaluating the risk of exposure to very expensive materials or when only limited quantities of a test material are available. These systems may also be used to expose rats and other small animals to radioisotopes in studies which evaluate the uptake, distribution, metabolism, and excretion of volatile xenobiotics.

Animals↗
PubMed1995

Three weeks' and six months' exposure to aromatic white spirit affect synaptosomal neurochemistry in rats.

The effects of 3 weeks' or 6 months' inhalation exposure of rats to aromatic white spirit 6 h/day, 5 days/week at 0, 400, or 800 ppm were studied. Synaptosomal neurochemistry was investigated as index of the in situ conditions in the presynaptic nerve terminal. In both studies, the relative and absolute yield of synaptosomal protein were significantly reduced in the two exposed groups. Both studies demonstrated increased synaptosomal noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) concentrations, high- affinity 5-HT uptake rate and uptake capacity. It is hypothesized that a reduced density and total number of synapses in situ may be functionally compensated by increased NA, DA, and 5-HT neurotransmitter release, or by increased activity of corresponding neurons. The increased synaptosomal 5-HT uptake rates and uptake capacities may explain the previously demonstrated increased global and regional neurotransmitter concentrations and the present finding of increased synaptosomal 5-HT concentrations. These changes are interpreted as an indication of toxic effect on the CNS function and are considered supportive of recent findings of electrophysiological changes and affected motor activity following 6 months' exposure to dearomatized white spirit followed by an exposure-free period.

Acetylcholinesterase↗
PubMedDate not supplied

A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings.

The human health risk for chronic illnesses involving multiple body systems following inhalation exposure to the indoor environments of water-damaged buildings (WDBs) has remained poorly characterized and the subject of intense controversy. The current study assessed the hypothesis that exposure to the indoor environments of WDBs with visible microbial colonization was associated with illness. The study used a cross-sectional design with assessments at five time points, and the interventions of cholestyramine (CSM) therapy, exposure avoidance following therapy, and reexposure to the buildings after illness resolution. The methodological approach included oral administration of questionnaires, medical examinations, laboratory analyses, pulmonary function testing, and measurements of visual function. Of the 21 study volunteers, 19 completed assessment at each of the five time points. Data at Time Point 1 indicated multiple symptoms involving at least four organ systems in all study participants, a restrictive respiratory condition in four participants, and abnormally low visual contrast sensitivity (VCS) in 18 participants. Serum leptin levels were abnormally high and alpha melanocyte stimulating hormone (MSH) levels were abnormally low. Assessments at Time Point 2, following 2 weeks of CSM therapy, indicated a highly significant improvement in health status. Improvement was maintained at Time Point 3, which followed exposure avoidance without therapy. Reexposure to the WDBs resulted in illness reacquisition in all participants within 1 to 7 days. Following another round of CSM therapy, assessments at Time Point 5 indicated a highly significant improvement in health status. The group-mean number of symptoms decreased from 14.9+/-0.8 S.E.M. at Time Point 1 to 1.2+/-0.3 S.E.M., and the VCS deficit of approximately 50% at Time Point 1 was fully resolved. Leptin and MSH levels showed statistically significant improvement. The results indicated that CSM was an effective therapeutic agent, that VCS was a sensitive and specific indicator of neurologic function, and that illness involved systemic and hypothalamic processes. Although the results supported the general hypothesis that illness was associated with exposure to the WDBs, this conclusion was tempered by several study limitations. Exposure to specific agents was not demonstrated, study participants were not randomly selected, and double-blinding procedures were not used. Additional human and animal studies are needed to confirm this conclusion, investigate the role of complex mixtures of bacteria, fungi, mycotoxins, endotoxins, and antigens in illness causation, and characterize modes of action. Such data will improve the assessment of human health risk from chronic exposure to WDBs.

Adult↗
PubMed1994

Deposition and retention of inhaled fibres: effects on incidence of lung cancer and mesothelioma.

A review of the literature on chronic inhalation studies in which rats were exposed to mineral fibres at known fibre number concentrations was undertaken to examine the specific roles of fibre length and composition on the incidences of both lung cancer and mesothelioma. For lung cancer, the percentage of lung tumours (y) could be described by a relation of the form y = a + bf + cf2, where f is the concentration of fibre numbers and a, b, and c are fitted constants. The correlation coefficients for the fitted curves were 0.76 for > 5 microns f/ml, 0.84 for > 10 microns f/ml, and 0.85 for > 20 microns f/ml. These seemed to be independent of fibre type. It has been shown that brief inhalation exposures to chrysotile fibre produces highly concentrated fibre deposits on bifurcations of alveolar ducts, and that many of these fibres are phagocytosed by the underlying type II epithelial cells within a few hours. Churg has shown that both chrysotile and amphibole fibres retained in the lungs of former miners and millers do not clear much with the years since last exposure. Thus, lung tumours may be caused by that small fraction of the inhaled fibres that are retained in the interstitium below small airway bifurcations where clearance processes are ineffective. By contrast, for mesothelioma, the (low) tumour yields seemed to be highly dependent upon fibre type. Combining the data from various studies by fibre type, the percentage of mesotheliomas was 0.6% for Zimbabwe (Rhodesian) chrysotile, 2.5% for the various amphiboles as a group, and 4.7% for Quebec (Canadian) chrysotile. This difference, together with the fact that Zimbabwe chrysotile has 2 to 3 orders of magnitude less than tremolite than Quebec chrysotile, provides support for the hypothesis that the mesotheliomas that have occurred among chrysotile miners and millers could be largely due to their exposures to tremolite fibres. The chrysotile fibres may be insufficiently biopersistent because if dissolution during translocation from their sites of deposition to sites where more durable fibres can influence the transformation or progression to mesothelioma.

Asbestos↗
PubMed1987

Effects of inhalation of ethylene dichloride on pulmonary defenses of mice and rats.

The effects of single or multiple inhalation exposures to ethylene dichloride (DCE) on the pulmonary defense systems of mice and rats were evaluated. Single exposures of mice to the threshold limit value of DCE (10 ppm) resulted in decreased pulmonary bactericidal activity to inhaled Klebsiella pneumoniae and increased mortality from Streptococcus zooepidemicus respiratory infection. A single exposure to 5 ppm DCE caused increased mortality from streptococcal pneumonia although bactericidal activity was not affected. Neither of these two parameters changed following single or five consecutive daily exposures to 2.5 ppm DCE. Single exposures to 10 or 100 ppm DCE did not affect mouse alveolar macrophage (AM) inhibition of the proliferation of a tumor target cell in vitro or AM in vitro phagocytosis of red blood cells. In rats, no effects were observed on pulmonary bactericidal activity. AM in vitro phagocytosis, AM cytostasis and cytolysis of tumor target cells, AM ectoenzymes, or blastogenesis of mitogen-stimulated rat T- and B-lymphocytes from lung-associated, mesenteric, and popliteal lymph nodes following single exposure to 100 or 200 ppm DCE or after twelve 5-hr exposures to 10, 20, 50, or 100 ppm DCE.

Administration, Inhalation↗
PubMed1998

Anaphylaxis to rabbit: a case report.

BACKGROUND: While rabbits are common as pets, severe allergic reactions to domestic rabbits in homes are unusual. Typically, allergic manifestations are mild to moderate allergic rhinitis, conjunctivitis, pruritus and/or asthma in laboratory animal caretakers with frequent exposure. METHODS: We report an atopic child with a severe allergic reaction following inhalant exposure to a rabbit. We performed percutaneous skin tests and determined serum-specific IgE to commercial preparation of rabbit epithelium and extracts of rabbit fur and serum. RESULTS: Percutaneous skin test was positive to rabbit epithelium. The patient had elevated serum-specific IgE to rabbit epithelium and fur but not to rabbit serum.

Air Pollution, Indoor↗
PubMed2003

Slight respiratory irritation but not inflammation in mice exposed to (1-->3)-beta-D-glucan aerosols.

Airway irritation effects after single and repeated inhalation exposures to aerosols of beta-glucan (grifolan) were investigated in mice. In addition, the effects on serum total immunoglobulin E (IgE) production and histopathological inflammation in the respiratory tract were studied. The beta-glucan aerosols provoked slight sensory irritation in the airways, but the response was not concentration dependent at the levels studied. Slight pulmonary irritation was observed after repeated exposures. No effect was found on the serum total IgE levels, and no signs of inflammation were seen in the airways 6 h after the final exposure. The results suggest that, irrespective of previous fungal sensitization of the animals, inhaled beta-glucan may cause symptoms of respiratory tract irritation but without apparent inflammation. Respiratory tract irritation reported after inhalation of fungi may not be entirely attributed to beta-glucan.

Aerosols↗
PubMed2005

Comparison of measured dermal dust exposures with predicted exposures given by the EASE expert system.

Estimation and Assessment of Substance Exposure (EASE) is a rule-based computer expert system used by regulatory authorities within the European Union to assist in assessing exposure for both new and existing substances. It can provide estimates of both inhalation exposure levels and dermal exposure levels to the hands and forearms. This article describes the results of a study in which measurements of workplace dermal zinc exposures were collected for an industry-wide risk assessment and also compared with the levels predicted by EASE. Measurements were obtained from subjects in seven different workplaces that were producing or working with zinc metal or zinc compounds. The work activities were grouped a priori into one of three categories used by EASE for dermal exposure assessment: 'non-dispersive use with intermittent direct handling', 'wide dispersive use with intermittent direct handling' and 'wide dispersive use with extensive direct handling'. The predicted exposure ranges for these categories are 0.1-1, 1-5 and 5-15 mg cm(-2) day(-1). Although the average measured exposure levels for each of the categories increased in line with the predictions from EASE, the model overestimated dermal exposure to the hands by a factor of approximately 50 when the mid-point of the EASE range was compared with the measured mean exposure. Furthermore, a significant additional exposure was found on other parts of the workers' bodies for which EASE does not provide any estimates. Interpretation of the dermal exposure data was complicated by the use of protective gloves, which might have limited the amount of zinc dust adhering to the workers' skin. However, observation of the work activities suggested that the pattern of glove use was such that they would not provide a consistent level of protection. This study provided an opportunity to collect a large amount of dermal zinc exposure data for risk assessment purposes and also enabled a dermal sampling method to be developed and assessed. There is no standard method for dermal dust exposure measurement, and the choice of method was a key factor in the exposure estimation process. With regard to comparison with the EASE predictions, it is possible that EASE could appear to perform more accurately if its predictions were compared with measurements obtained using surrogate skin sampling methods. However, we believe that such sampling can provide a gross overestimate of the dust on the skin surface. We suggest that further development of the EASE system is necessary to ensure that it better reflects whole-body dermal exposures to dusts.

Dermis↗
PubMed2005

Development of a biologically relevant dermal sampler.

There are currently no appropriate methods for measuring dermal exposure to volatile agents. To address this we have produced a prototype Institute of Occupational Medicine (IOM) dermal sampler consisting of an adsorbent sandwiched between a permeable membrane and an impervious backing. The concentration of solvent on the membrane surface may be estimated from the mass collected on the adsorbent and the known permeation rate through the membrane. We have developed the prototype IOM dermal sampler for measurement of toluene exposures. Evaluation of the prototype sampler was undertaken in two stages: laboratory performance in controlled exposure situations and two short-field evaluations, which included simultaneous measurement of inhalation exposure. In all cases we compared the prototype IOM dermal sampler with activated charcoal cloth (ACC). Laboratory trials were split into spray, pour and immersion tests. The data from these suggest that the sampler responds to concentration rather than the mass on the surface of the sampler. The field study showed that the prototype sampler was suitable for measuring dermal exposure. However, the mean permeation rate of the best membrane was 78 000 mug cm(-2) h(-1), which is higher than the permeation rate through skin. This high permeation rate created difficulties throughout the study, particularly as it allowed the adsorbent to become rapidly saturated. The prototype IOM dermal sampler is the first practical dermal exposure sampler to mimic uptake through the skin. The sampler gave reproducible results in the laboratory and field trials. Future work is required to identify a less permeable membrane, which has characteristics closer to that of human skin. Additionally, a higher capacity adsorbent would be desirable. We have demonstrated a major difference when calculating the total contribution to body burden via the dermal exposure pathway using the prototype IOM dermal sampler and ACC patches, 1.5% of the total body burden compared with 95%. The prototype IOM dermal sampler provides a more biologically relevant exposure metric than the alternatives.

Air Pollutants, Occupational↗
PubMed2005

Use of a chemical probe to increase safety for human volunteers in toxicokinetic studies.

To avoid interspecies extrapolation in toxicokinetics and drug development, it is convenient to directly develop human data. In that case, exposure dose should pose null or negligible risk to the exposed individual, but still be sufficiently high to allow quantification. We propose to reduce the dose received by human volunteers during exposure, and to compensate for loss of information by exposing the same volunteers to a nontoxic agent. This method was applied to develop 1,3-butadiene (BD) exposure protocols for humans. To study the potential of such a procedure, we worked with simulated data. Three exposure times (20, 10, and 5 minutes) and four exposure concentrations (2, 1, 0.8, and 0.5 ppm) were used to define 12 inhalation exposure scenarios for BD. Isoflurane was used as a probe, with simulated exposure of 20 subjects to 20 ppm isoflurane during 15 minutes. Isoflurane or BD-exhaled air concentrations were supposed to be measured 10 times. A three-compartment physiological toxicokinetic model was used to jointly describe BD and isoflurane data. For each subject, BD data were analyzed, in a Bayesian framework, either alone or together with the isoflurane data. The precision of BD metabolic rate constant or fraction metabolized was increased, and bias reduced, when BD and probe data were considered jointly. An exposure to 10 ppm x min BD and 300 ppm x min isoflurane gave equivalent precision and bias as a unique exposure to 40 ppm x min BD. The BD dose received by volunteers could therefore be at least quartered if BD exposure was supplemented with that of a probe.

Air Pollutants↗