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PubMed1997

Toxicokinetics in the National Toxicology Program.

Toxic responses to test chemicals are known to be dependent on the exposure route, the kinetic behavior of the chemical, and the dose used in the toxicology study. Therefore, knowledge of internal dose is indispensable for the interpretation of toxicology study results, for the facilitation of interspecies scaling, and for risk assessment. By monitoring the blood and/or tissue concentrations of test chemical and/or metabolites versus time after administration of study chemicals by different routes, the bioavailability and kinetic characteristic of test chemicals can be readily obtained. This data can define the so-called linear dose range using area under the plasma concentration versus time curve, clearance, or other related toxicokinetic parameters, and can also be used to predict the possible bioaccumulation under multiple dose regimes. Changes in kinetic parameters after multiple exposures indicate alteration in how the animal handles the chemical (e.g., that there was enzyme induction or inhibition). A recommended approach for conducting toxicokinetic studies generally involves three steps. Step 1 is a preliminary study, which uses a minimum number of animals to estimate the range of blood/tissue concentrations, the required quantitation limit for the analytical method, and the optimal sampling times for the definitive toxicokinetic studies. Step 2 is the definitive study and generates blood and/or tissue concentration data for calculating the toxicokinetic parameters. Step 3 is the toxicokinetic study conducted in conjunction with the toxicology study to determine the internal dose and the effects of age and continuous exposure on kinetic parameters. Examples of the application of NTP toxicokinetic evaluations were also presented in this chapter, demonstrating their use in the design and interpretation of toxicology studies.

Animals↗

PubMed2003

Sex differences in the toxicokinetics of inhaled solvent vapors in humans 2. 2-propanol.

The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of 2-propanol vapor. Nine women and eight men were exposed on different occasions for 2 h during light physical exercise (50 W) to 2-propanol (350 mg/m3) and to clean air (control exposure). The level corresponds to the Swedish occupational exposure limit. 2-Propanol and its metabolite acetone were monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. Body fat and lean body mass were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes were determined by PCR-based assays for alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1). The CYP2E1 phenotype was assessed by the 2-h plasma 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio in vivo. The toxicokinetic profile in blood was analyzed using a one-compartment population model. The following sex differences were significant at the p = 0.05 level (Student's t test). The respiratory uptake was lower and the volume of distribution smaller in females. The women had a slightly shorter half-time of 2-propanol in blood and a higher apparent total clearance when corrected for body composition. However, women reached approximately four times higher 2-propanol levels in exhaled air at 10-min postexposure and onward. Acetone in blood was markedly higher in females than in males in the control experiment and slightly higher following exposure to 2-propanol. A marked sex difference was that of a 10-fold higher in vivo blood:breath ratio in men, suggesting sex differences in the lung metabolism of 2-propanol. The most marked sex difference was that of salivary acetone, for which an approximately 100-fold increase was seen in women, but no increase in men, after exposure to 2-propanol compared to clean air. The toxicokinetic analysis revealed no significant differences in toxicokinetics between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates several sex differences in the inhalation toxicokinetics of 2-propanol. Most of these differences are consistent with anatomical differences between women and men. However, body build can not explain the sex differences in 2-propanol levels in expired air and acetone in saliva.

2-Propanol↗

PubMed2006

The role of toxicokinetics in xylene-induced ototoxicity in the rat and guinea pig.

In the rat, some aromatic solvents cause a high level of ototoxicity that is characterized by damage to outer hair cells in the cochlea, which results in irreversible hearing loss. However, there is a vast difference in their potency. Among the three isomers of xylene, only para-xylene has been shown to be ototoxic in the rat. Moreover, all the species do not show the same susceptibility to ototoxic solvents, the rat being the most susceptible and the guinea pig seeming resistant to this ototoxic effect. The objective of the study was to determine whether toxicokinetic factors could explain the differences in ototoxicity observed among the three isomers of xylene in the rat and the species-dependent ototoxicity in the rat and the guinea pig. Blood and brain concentrations of each isomer were monitored in Sprague-Dawley rats treated orally by gastric intubation with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg (an ototoxic dosage for para-xylene) of each isomer. Moreover, histology of the cochlea was carried out and the toxicokinetics of meta-xylene was monitored in rats treated with a single dose or a 10 day-repeated treatment of 16.94 mmol/kg meta-xylene, a non-ototoxic isomer. Similarly, histology of the cochlea was carried out and the toxicokinetics of para-xylene was followed in guinea pigs treated by gavage with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg para-xylene. Finally, the blood and brain concentrations of para-xylene were measured in both the rats and the guinea pigs after a 4-h exposure to 1800 ppm of para-xylene. Among the three isomers studied, para-xylene yielded the highest blood and brain concentrations in the acutely and repeatedly exposed rats. When given a high dosage of meta-xylene (16.94 mmol/kg), the rats showed blood and brain concentrations of meta-xylene in the same order as those obtained with 8.47 mmol/kg para-xylene, but no outer hair cell loss was observed. No outer hair cell loss was observed in the guinea pigs treated with para-xylene. Whatever the exposure pattern, the blood and brain concentrations of para-xylene in the rats were 3.1-9.5 times higher than those measured in the guinea pigs. These results indicate that toxicokinetic factors cannot explain the differences in ototoxicity observed with the three isomers in the rat. However, they suggest that the differences in susceptibility to para-xylene observed between the rats and the guinea pigs might be due to toxicokinetic factors.

Animals↗

PubMed2003

Mechanistic and toxicokinetic data reducing uncertainty in risk assessment.

Risk characterization comprises hazard identification describing the intrinsic toxic potential of a chemical, knowledge of dose-response-relationships, as well as of toxicokinetics describing quantitatively the relation between external and internal dose and exposure assessment. Compounds that induce reversible effects, which are repaired during and after exposure, are considered thresholded and allow definition of a NOEL. Biological reactive intermediates of chemicals have the potential to bind covalently to cellular macromolecules like proteins and DNA. Such interaction may not be repaired completely. If damage is not repaired, the effect persists and accumulates upon repeated exposure. In such cases a NOEL cannot be determined. Thus, in the risk assessment process, data on covalent binding (CB) are of qualitative and together with toxicokinetics of quantitative significance. Qualitatively, CB, especially with DNA and in correlation with this to proteins, is indicative for an irreversible and non-thresholded mutagenic and carcinogenic effect. Absence or presence of CB assists to differentiate between primarily genotoxic and thresholded non-genotoxic carcinogens. Quantitatively, toxicokinetics together with CB are used to quantify internal exposure and target dose, which is a prerequisite for species-species extrapolation, and for extrapolation from high dose to low dose. For example, the toxicokinetics of the reactive intermediates of styrene and ethylene have been determined in rodents and humans and modeled to predict dose-responses of internal exposure. It is described in this communication that such information, together with other parameters like cell proliferation as a result of cytotoxicity, is the basis for quantitative risk assessment of human exposure to these compounds. Also for chlorobenzene, the relevance of toxicokinetics for estimating the human health risk is demonstrated.

Animals↗

PubMed1992

Toxicokinetics of mercuric chloride and methylmercuric chloride in mice.

Future human exposure to inorganic mercury will probably lead to a few individuals occupationally exposed to high levels and much larger populations exposed to low or very low levels from dental fillings or from food items containing inorganic mercury; human exposure to methylmercury will be relatively low and depending on intake of marine food. Ideally, risk assessment is based on detailed knowledge of relations between external and internal dose, organ levels, and their relation to toxic symptoms. However, human data on these toxicokinetic parameters originate mainly from individuals or smaller populations accidentally exposed for shorter periods to relatively high mercury levels, but with unknown total body burden. Thus, assessment of risk associated with exposure to low levels of mercury will largely depend on data from animal experiments. Previous investigations of the toxicokinetics of mercuric compounds almost exclusively employed parenteral administration of relatively high doses of soluble mercuric salts. However, human exposure is primarily pulmonary or oral and at low doses. The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice. Major findings using this model are discussed in relation to previous knowledge. The toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex, whereas the mouse strain used is less important. The "true absorption" of a single oral dose of HgCl2 was calculated to be about 20% at two different dose levels. Earlier studies that did not take into account the possible excretion of absorbed mercury and intestinal reabsorption during the experimental period report 7-10% intestinal uptake. The higher excretion rates observed after oral than after intraperitoneal administration of HgCl2 are most likely due to differences in disposition of systemically delivered and retained mercury. After methylmercury administration, mercury excretion followed first-order kinetics for 2 wk, independently of administration route, strain, or sex. However, during longer experimental periods, the increasing relative carcass retention (slower rate of excretion) caused the elimination to deviate from first-order kinetics. Extensive differences in the toxicokinetics of methylmercury with respect to excretion rates, organ deposition, and blood levels were observed between males and females.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗

PubMedDate not supplied

Concomitant toxicokinetics: techniques for and interpretation of exposure data obtained during the conduct of toxicology studies.

Toxicokinetic analyses have become a routine component of preclinical toxicology studies with pharmaceutical candidates. Evaluation of plasma and/or tissue samples from animals used in toxicology studies (or concurrent satellite groups) provides information on dose proportionality, the potential for dose accumulation, and the sex and species differences in distribution and elimination. Toxicokinetic information is used by toxicologists, toxicology management, clinicians, institutional review boards, regulatory agencies to ensure that exposure has occurred in animal species to a sufficient extent to minimize the potential risk of toxicities in humans. The requirements for descriptive toxicokinetics change depending on the stage of development of new drug candidates. Early in development, documentation of exposure in 1 species and sex of laboratory animal might be enough to justify preliminary development costs and initiation of product development. Later in development, it becomes necessary to know how new drug candidates are distributed and eliminated following subchronic and chronic administration in multiple species and both sexes. Finally, knowledge of toxicokinetics is used to help establish doses in long-term oncogenicity studies. Scientific, public, and regulatory pressures have recently dictated that the number of animals used in toxicology studies be closely monitored and minimized. Toxicokinetic evaluation of new drug candidates by a staggered sampling design is now routinely performed in our laboratories to maximize information obtained while reducing animal use.

Animals↗

PubMed2001

Toxicokinetics and toxicity of zinc under time-varying exposure in the guppy (Poecilia reticulata).

Levels of toxic substances released into the environment are often highly variable and fluctuate over time. The present study deals with a simple type of time-variable exposure, diluted pulse. We determined toxicokinetic parameters of zinc in guppy fish (Poecilia reticulata) and evaluated the applicability of a toxicokinetics-based survival model developed earlier. In the toxicokinetics experiment, zinc was rapidly taken up and released again; the half-life in fish was only 1.5 d. In the toxicity experiments with diluted-pulse exposure, survival leveled off to a baseline level, which in accordance with the model is explained by the dilution of zinc. The model fitted reasonably well for the lower initial concentrations but tended to overestimate survival rates at the higher concentrations. Toxicokinetic parameters estimated from changes in survival were close to values estimated from measured zinc concentrations in water. Elimination rates during pulse exposure varied from 0.434 to 0.488 d(-1) and corresponded very well to the elimination rate during constant exposure (0.463 d(-1)). Ultimate LC50 values were estimated as 6.40 and 9.10 mg/L. These results suggest that toxicity experiments with a simple, time-varying exposure can be used as an alternative to conventional, constant-exposure experiments. Toxicokinetic parameters and toxicological endpoints can still be estimated in static bioassays with decreasing exposure if the concentration in the medium is measured. At the same time, diluted-pulse experiments may simulate exposure from discharges in the field better than constant-exposure experiments.

Animals↗

PubMedDate not supplied

Distinguishing animal subsets in toxicokinetic studies: comparison of non-linear mixed effects modelling with non-compartmental methods.

The purpose of this study was to compare the ability of non-compartmental analysis and compartmental mixed effects modelling (MEM) to determine the existence and magnitude of exposure differences (i.e. exposure ratio estimates) between subsets of animals during destructive toxicokinetic studies. Data from five toxicokinetic studies of an experimental compound were analysed using a linear trapezoidal calculation of the area under the curve (non-compartmental analysis) or modelled using MEM. With the non-compartmental method the Bailer-Satterthwaite approximation was used to construct confidence intervals around the exposure estimates of each subset of animals and these were used to determine if exposure differed between the subsets. The MEM analyses were performed on the full datasets and on datasets with arbitrary reductions in the number of animal replicates. With MEM, additional model parameters were used to differentiate between subsets of animals, and were incorporated only if they were justified statistically. Estimates of the existence and magnitude of exposure differences between animal subsets were similar with the two techniques. The MEM analyses were influenced only marginally by substantial reductions in the number of animals studied and were less compromised by extremely limited or unbalanced data. These analyses show that MEM and non-compartmental methods are similarly effective at detecting exposure differences between animal subsets in toxicokinetic studies. Estimates provided by both methods were influenced by the degree of variance in the data. These results support the proposition that it may be possible to reduce the number of animals employed in toxicokinetic studies if MEM is used.

Animals↗

PubMed1998

The effect of toxicokinetics on murine mercury-induced autoimmunity.

Mercury induces autoantibodies to the nucleolar protein fibrillarin (ANoA) in genetically susceptible (H-2AS) mouse strains. This study examines the importance of mercury toxicokinetics for the induction and strength (titer) of these autoantibodies. Female mice of the inbred strains A.SW and B10.S (H-2AS on the A and C57BL/10 genetic background, respectively) and A.TL and B10.TL (H-2Ak on the A and C57BL/10 background) were treated with 203HgCl2 in a dose of 1, 5, or 16 mg Hg/L drinking water for 56-70 days. Whole-body retention of 203Hg was monitored throughout the experimental period. Mercury accumulation in kidney, liver, heart, spleen, and brain was determined at end of the experiment when blood samples were also obtained for determination of ANoA. The drinking water consumption showed a limited variation between the strains and the dose groups. Therefore, intake of mercury did not vary much between the strains at a given dose level. The whole-body retention of mercury reached steady state after 4-5 weeks. In general, the B10.S and B10.TL strains showed a lower whole-body retention and deposition of mercury in the kidney and the liver, compared with the A.SW and A.TL strains given the same dose of mercury. The B10.S strain showed a threshold for induction of ANoA at 5 mg Hg/L, whereas ANoA were still seen in A.SW mice given 1 mg Hg/L. Taken together, this is compatible with a less efficient elimination of mercury in the A.SW and A.TL strains, which was also supported by the higher ratio between whole-body retention and intake of mercury in these strains. These findings indicate that genes residing outside the H-2 (MHC) complex play an important role for regulating mercury toxicokinetics, the A genes conferring higher accumulation of mercury in the body than the B10 genes. In mice congenic with regard to the susceptible H-2AS haplotype, a highly significant correlation (P<0.01) existed between on the one hand the whole-body retention and organ accumulation of mercury and on the other hand the titer of ANoA. We conclude that mercury toxicokinetics differs significantly among inbred mouse strains. The differences in toxicokinetics are regulated by non-H-2 genes and correlate with the autoimmune response in the genetically susceptible strains: quantitatively as the titer of the ANoA and qualitatively as different threshold doses for induction of ANoA by mercury.

Animals↗

PubMed1996

Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in two substrains of male Long-Evans rats after intravenous injection.

Toxicokinetics of a nontoxic intravenous dose of 14C-labeled TCDD were studied in two substrains of Long-Evans (L-E) rats with a fivefold difference in sensitivity in terms of TCDD-induced mortality. The Turku/AB Long-Evans rat (T L-E) is the most sensitive rat strain with an oral LD50 of 17.7 microgram/kg, whereas the Charles River Long-Evans rat (CR-L-E) is a more resistant strain (oral LD50 95.2 microgram/kg). Samples of 18 tissues were collected 1, 2, 4, 8, 16, and 32 days after dosing and analyzed for radioactivity. Body weight and fecal and urinary excretion of radioactivity were monitored daily during the 32-day study period. CR L-E rats grew significantly faster than T L-E rats, increasing their body weight by 60% in 32 days compared with only 16% in T L-E rats. This difference was not caused by toxicity, because the weight gain was identical in control and TCDD-treated rats of both substrains. Tissue concentrations of [14CC]TCDD-associated radioactivity and area under the curve (AUC) values were lower in CR L-E than in T L-E rats. The most pronounced differences were found in thymus, white adipose tissue, brown adipose tissue, and adrenals. The decrease of TCDD concentration in tissues was faster in CR L-E than in T L-E rats, whereas fecal and urinary excretion was faster in T L-E than in C L-E rats. Elimination half-life was 20.2 days in T L-E rats and 28.9 days CR L-E rats. Differential toxicokinetics of TCDD in the two L-E substrains provide a likely explanation for the greater sensitivity of the T L-E strain, since observed differences in tissue concentrations and AUC values are in good agreement with the difference in susceptibility. In addition to the more efficient tissue uptake of TCDD in T L-E rats than in CR L-E rats, the major contributing factor to differences in toxicokinetics seems to be a differential growth rate (dilution by growth), which in turn appears to provide an explanation for the difference in susceptibility. More rapid excretion of TCDD in T L-E rats than in CR L-E rats is clearly a result of higher tissue concentrations in T L-E rats. However, this faster excretion rate is not sufficient to counterbalance the much slower dilution by growth in T L-E rats than in CR L-E rats. Thus, dilution by growth can be a more important factor in determining the toxicokinetics and toxicity of TCDD in rodents than is excretion.

Animals↗

PubMed2002

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone.

Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.

Animals↗

PubMed2002

Inhalation toxicokinetics of p-dichlorobenzene and daily absorption and internal accumulation in chronic low-level exposure to humans.

Inhalation toxicokinetics of p-dichlorobenzene ( p-DCB) in humans was evaluated, and the amounts of daily absorption and internal accumulation were estimated in order to obtain fundamental data for the risk assessment of chronic low-level exposure in the general population. Seven male subjects continuously inhaled about 2.5 ppm of p-DCB vapor for 1 h, and the concentration-time courses of p-DCB in their exhaled air and serum and of urinary 2,5-dichlorophenol (2,5-DCP), a major metabolite of p-DCB, were examined. The toxicokinetics of p-DCB was evaluated on the basis of the time courses using a linear two-compartment model. The amounts of p-DCB absorbed daily and the internal accumulation in chronic low-level exposure were extrapolated using the estimated toxicokinetic parameters. p-DCB was transferred from inhaled air to the body with a constant high absorption rate during exposure. The major route for elimination from the body was urinary excretion followed by metabolism, not exhalation. However, during 9-11 h after the start of exposure, the fraction of p-DCB excreted in urine was only 5-16% of the amount absorbed. Furthermore, most of the absorbed p-DCB seemed to be distributed rapidly to the tissues, such as fat, according to toxicokinetic analysis. Consequently, p-DCB seems to require a long time to be completely eliminated from the body. The amounts of daily absorption and internal accumulation were extrapolated to average 0.27 mg/day and 2.9 mg, respectively, in the subjects exposed chronically to 1 ppb of p-DCB. The amount absorbed daily agreed approximately with that extrapolated from rats which inhaled p-DCB in our previous study.

Absorption↗

PubMed2000

Toxicokinetics of 2,4,5-trichlorophenol and benzo(a)pyrene in the clam Pisidium amnicum: effects of seasonal temperatures and trematode parasites.

Several biotic and abiotic stress factors may affect aquatic organisms simultaneously. However, not much is known about the effects of, e.g., low temperatures and parasite infections on the toxicokinetics of organic hydrophobic chemicals. Here we studied the accumulation and depuration of [(14)C]2,4,5-trichlorophenol (TCP) and [(3)H]benzo(a)pyrene (BaP) in the sediment-dwelling freshwater clam Pisidium amnicum. Experiments were made in October (+15 degrees C), April (+4 degrees C), and July (+15 degrees C) both with uninfected clams and clams infected with Bunodera luciopercae (Trematoda). The accumulation rate for both chemicals was slower at 4 degrees C than at 15 degrees C. The depuration of TCP was biphasic, and the slowest depuration occurred at 4 degrees C. For BaP, the depuration was very slow and monophasic at all temperatures. The highest BCFs for both chemicals were found in July at 15 degrees C. Surprisingly, the BCFs for TCP were higher in April at 4 degrees C than in October at 15 degrees C. For BaP, no steady-state was reached in April. Differences in chemical toxicokinetics between the infected and uninfected clams were only minor. However, for both chemicals a trend of slightly lower BCFs in the infected clams was found. In conclusion, low temperatures modify the toxicokinetics of organic chemicals in P. amnicum and the effects depend on hydrophobicity of the chemical. The effects of parasites on toxicokinetics seem to be small.

Algorithms↗

PubMed1987

Toxicokinetics of the four stereoisomers of the nerve agent soman in atropinized rats--influence of a soman simulator.

The toxicokinetics of the four stereoisomers of C(+/-)P(+/-)-soman were investigated in anesthetized, atropinized, and artificially ventilated rats at iv doses of 6 (495 micrograms/kg) and 3 LD50. By integration of a thermodesorption/cold trap injector into our GLC analysis, the soman stereoisomers could be followed in rat blood down to a minimum detectable concentration, i.e., 1.5 pg/ml (8.3 pM), 55-fold lower than that published previously. This new detection limit is probably near or below the minimum concentration relevant for survival. Whereas C(+)P(+)-soman disappears in vivo from rat blood within 0.25 min, the toxicokinetics of C(-)P(+)-soman could be described by a two-compartment model, with a biological half-life of 1-1.5 min. The extremely toxic C(+/-)P(-)-isomers could be followed in rat blood for greater than 4 and 2 hr at doses of 6 and 3 LD50, respectively. The toxicokinetics of the P(-)-isomers are best described with a three-compartment model, with terminal half-lives of 40-64 and 16-22 min at doses of 6 and 3 LD50, respectively. Administration of a 13.6-fold molar excess of the soman simulator 1,2,2-trimethylpropyl dimethylphosphinate (PDP) 10 min prior to administration of 6 LD50 of C(+/-)P(+/-)-soman reduces the terminal half-lives of the C(+/-)P(-)-isomers to the values measured at the dose of 3 LD50 without PDP pretreatment. Previous investigations showed that, without PDP pretreatment, rats suffer from endogenous reintoxication 4-6 hr after initially successful therapy, at C(+/-)P(+/)-soman doses greater than or equal to 6 LD50. Both this reintoxication phenomenon due to the presence of toxicologically significant C(+/-)P(-)-soman levels up to 4 hr after intoxication and its antagonism via PDP pretreatment can be understood on the basis of our toxicokinetic measurements. This shows that such investigations can contribute to insight into the toxicology of C(+/-)P(+/-)-soman and to a better treatment of intoxications with this agent.

Animals↗

PubMed1988

Toxicokinetics in the evaluation of toxicity data.

Toxicokinetics provides a powerful tool, which is not used sufficiently in the conduct and interpretation of animal toxicity studies. In selecting doses for toxicity studies toxicokinetic data can be used effectively. The tools of toxicokinetics are limited only by the toxicologists' understanding of basic biologic mechanisms. More knowledge on mechanisms of action implicates the possibility of more detailed toxicokinetic models. Physiologically based pharmacokinetic models are valuable in the interpretation of animal toxicity studies. They provide a physiological basis for extrapolating between species and routes of administration, and the future use of these models in setting acceptable levels of exposure for non-cancer toxicity in humans deserves serious consideration.

Animals↗

PubMed2003

Sex differences in the toxicokinetics of inhaled solvent vaporsin humans 1. m-Xylene.

The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of m-xylene vapor. Seventeen healthy volunteers (nine women and eight men) were exposed to m-xylene (200 mg/m3) and to clean air (control exposure) on different occasions during 2 h of light physical exercise (50 W). The chosen level corresponds to the occupational exposure limit (8-h time weighted average) in Sweden. m-Xylene was monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. m-Methylhippuric acid (a metabolite of m-xylene) was analyzed in urine by high-performance liquid chromatography. Body fat and lean body mass (LBM) were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes and/or phenotypes of cytochromes P450 2E1 and 1A1, glutathione transferases M1 and P1, and epoxide hydrolase were determined. The toxicokinetic profile in blood was analyzed using a two-compartment population model. The area under the concentration-time curve (AUC) of m-xylene in exhaled air postexposure was larger in women than in men. In addition, the excretion via exhaled air was significantly higher in women when correcting for body weight or LBM. In contrast, the men had a significantly higher volume of distribution, excretion of m-methylhippuric acid in urine, and AUC of m-xylene in urine. The toxicokinetic analyses revealed no differences between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates small sex differences in the inhalation toxicokinetics of m-xylene, which can be explained by body build.

Administration, Inhalation↗

PubMed1996

Aluminum toxicokinetics.

In this study of the toxicokinetics of aluminum we have examined some of the fundamental issues that currently define our understanding of the toxicology of aluminum in humans. There is a vast literature on this subject, and it was not our aim to review this literature but to use it to develop our understanding of the toxicokinetics of aluminum and to identify critical and unresolved issues related to its toxicity. In undertaking this task we have chosen to define the term toxicokinetics to encompass those factors that influence both the lability of aluminum in a body and the sites at which aluminum is known to accumulate, with or without consequent biological effect. We have approached our objective from the classical pharmacological approach of ADME: the absorption, distribution, metabolism, and excretion of aluminum. This approach was successful in identifying several key deficits in our understanding of aluminum toxicokinetics. For example, we need to determine the mechanisms by which aluminum crosses epithelia, such as those of the gastrointestinal tract and the central nervous system, and how these mechanisms influence both the subsequent transport and fate of the absorbed aluminum and the concomitant nature and severity of the biological response to the accumulation of aluminum. Our hope in highlighting these unresolved issues (summarized in Table 1) is that they will be addressed in future research.

Absorption↗

PubMed2001

Toxicokinetics of inhaled benzo[a]pyrene: plasma and lung bioavailability.

Bioavailability and toxicokinetic studies are essential in order to establish dose-response relationships of widely distributed environmental toxicants such as benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon. Fischer 344 rats were exposed for 4 h (via nose-only inhalation) to aerosol exposure concentrations of 0.1, 1.0, and 2.5 mg/m(3) of BaP absorbed onto carbon black particles using a state-of-the-art model aerosol generation system. Nominal and chamber concentrations of the particulate aerosol were determined gravimetrically with a seven-stage cascade impactor. The average aerosol for the 3 exposure concentrations used in this study exhibited a trimodal distribution with 93% cumulative mass less than 15.85 microm, 89% cumulative mass less than 10 microm, 55.3% cumulative mass less than 2.5 microm, and 38% less than 1 microm. Fifty-five percent of the aerosol had a cumulative mass less than PM(2.5) and the mass median aerodynamic diameter (MMAD) -/+ geometric standard deviation (GSD) for this mode was 1.7 -/+ 0.085 microm. Plasma and lung samples were collected at 30, 60, 120, and 240 min postexposure. The concentrations of BaP parent compound and metabolites were determined by high-performance liquid chromatography. The toxicokinetic parameters were computed from the time course of plasma BaP concentration. The bioavailability of BaP increased as a function of exposure concentration, and toxicokinetic analysis indicates first-order pharmacokinetics for BaP. However, some toxicokinetic parameters such as clearance and volume of distribution remained constant throughout the duration of the postexposure period. BaP and its metabolite concentrations in plasma peaked at 1 h postexposure. At 240 min postexposure, only trace levels of BaP remained in the plasma. The BaP metabolites in the lung showed an identical trend where no parent compound was detected. Among the metabolites detected, BaP 4,5-, 7,8-, and 9,10-dihydrodiols, 3-OH-BaP, and 9-OH-BaP were predominant.

Administration, Inhalation↗