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PubMedDate not supplied

Toxicokinetics and physiologically based toxicokinetics in toxicology and risk assessment.

Toxicokinetics is the study of kinetics of absorption, distribution, metabolism, and excretion of a xenobiotic under the conditions of toxicity evaluation. Conventional toxicokinetics uses the hypothetical compartments, and the model is composed of rate equations that describe the time course of drug and chemical disposition. The utility of toxicokinetics in toxicity evaluation and interpretation of animal toxicology data is emerging as an important tool in product discovery and development. With implementation of the International Conference on Harmonization (ICH) guidelines on systemic exposure and dose selection, toxicokinetics have been integrated in routine toxicity evaluations. Although traditional compartmental/noncompartmental models are generally adequate for assessing systemic exposure, they are unable to the predict time course of drug disposition in target tissues and often fail to relate systemic drug levels to a biological response. Physiologically based toxicokinetic (PB-TK) models address this deficiency of traditional compartmental models. PB-TK models are the kinetic models of the uptake and disposition of chemicals based on rates of biochemical reactions, physiological and anatomical characteristics. These models, when developed appropriately, can predict target organ drug distribution in different species under variety of conditions. This minireview discusses the basic principles, and applications of traditional compartmental toxicokinetic and physiologically based toxicokinetics (PB-TK) models in drug development and risk assessment. Special emphasis will be placed on discussion related to interpretation of the ICH guidelines related to toxicokinetics and the utility of toxicokinetics data in dose selection for toxicity and carcinogenicity studies. The utility of PB-TK models in risk assessment of methylene chloride, vinyl chloride, retinoic acid, dioxin, and inhaled organic esters is discussed.

Animals↗

PubMed2003

Application of physiologically based toxicokinetic modelling to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of toluene in rats.

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.

Administration, Inhalation↗

PubMed2000

Toxicokinetics in drug development: an overview of toxicokinetic application in the development of PNU-101017, an anxiolytic drug candidate.

The importance of toxicokinetics in the drug development has been identified in the last decade. The main objectives of toxicokinetics in general are to define the drug bioavailability, dose proportionality, gender differences, and species differences in pharmacokinetics and metabolism, from which the target organ toxicity can be predicted and the safety doses in the first human clinical trial can be established. Toxicokinetic studies may also serve as a tool for the toxicologic pathologist in understanding models used for predicting and assessing drug-related toxic response. Toxicokinetics/toxicodynamics are critical to investigating the toxicological mechanism and understanding the comparative toxicity between animals and humans. This report presents an overview of the application of toxicokinetics and its impact in the drug development of PNU-101017, a drug candidate for the treatment of anxioety. Serial specifically designed toxicokinetic studies identified a steep dose-response relationship between the clinical signs and PNU-101017 serum or CSF concentrations, characterized the centrally mediated respiratory depression as the toxicity leading to the lethality, and demonstrated marked species differences in the sensitivity to the toxic effects. These findings lead to a termination of PNU-101017 development due to the safety concern in humans.

Animals↗

PubMed2002

Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives.

This paper reviews the toxicokinetics of amphetamines. The designer drugs MDA (methylenedioxy-amphetamine, R,S-1-(3;,4;-methylenedioxyphenyl)2-propanamine), MDMA (R,S-methylenedioxymethamphetamine), and MDE (R,S-methylenedioxyethylamphetamine), as well as BDB (benzodioxolylbutanamine; R,S-1-(1;,3;-benzodioxol-5;-yl)-2-butanamine or R,S-1-(3;,4;-methylenedioxyphenyl)-2-butanamine) and MBDB (R,S-N-methyl-benzodioxolylbutanamine), were taken into consideration, as were the following N-alkylated amphetamine derivatives: amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, methamphetamine, prenylamine, and selegiline. English-language publications from 1995 to 2000 were reviewed. Papers describing identification of metabolites or cytochrome P450 isoenzyme-dependent metabolism and papers containing pharmacokinetic/toxicokinetic data were considered and summarized. The implications of toxicokinetics for toxicologic assessment or for interpretation in forensic cases are discussed.

Amphetamines↗

PubMed1989

Predicting toxicokinetic parameters in humans from toxicokinetic data acquired from three small mammalian species.

Values for the independent kinetic variables, clearance (CL) and volume of distribution (V), for six xenobiotics--antipyrine, ethosuximide, phencyclidine, theophylline, valproic acid and warfarin--were culled from the literature for each of three small subhuman species and for humans, and then allometrically scaled. Scaling was performed in two ways. First, using kinetic data acquired for three small subhuman species and for man, scaled parameters were observed for goodness of fit to a standard allometric expression. Second, scaled parameters were averaged for three subhuman species. Mean scaled kinetic parameters from only three species were used to predict half-life values of the xenobiotics in humans. Finally, predicted percentages of the xenobiotic burdens remaining in humans at the end of four allometrically-predicted half-lives were compared with the expected percentages of remaining xenobiotic based upon four actual half-lives in humans. The results suggest that it may be feasible to estimate, using three small subhuman species, allometrically-derived toxicokinetic parameters of some substances in man with sufficient accuracy to be of practical value.

Animals↗

PubMed1991

Toxicokinetics of inhaled 1,3-butadiene in monkeys: comparison to toxicokinetics in rats and mice.

1,3-Butadiene is a potent carcinogen in mice and a weaker carcinogen in rats. People are exposed to butadiene through its industrial use--largely in rubber production (over 3 billion pounds of butadiene were produced in 1989)--and because it is common in the environment, occurring in cigarette smoke, gasoline vapor and in the effluents from fossil fuel incineration. Epidemiological studies have provided some evidence for butadiene carcinogenicity in people. Differences in the uptake and metabolism of inhaled butadiene between rodents and primates, including people, might be reflected in differences in its toxicity. In order to compare uptake and metabolism in primates to that in rodents--for which data were already available--we exposed cynomolgus monkeys (Macaca fascicularis) to 14C-labeled butadiene at concentrations of 10.1, 310 or 7760 ppm for 2 hr. Exhaled air and excreta were collected during exposure and for 96 hr after exposure. The uptake of butadiene as a result of metabolism was much lower in monkeys than in rodents. For equivalent inhalation exposures, the concentrations of total butadiene metabolites in the blood were 5-50 times lower in monkey than in the mouse, the more sensitive rodent species, and 4-14 times lower than in the rat. If the toxicokinetics of butadiene in people is more like that of the monkey than that of rodents, then our data suggest that people will receive lower doses of butadiene and its metabolites than rodents following equivalent inhalation exposures to butadiene. This has important implications for assessing the risk to humans of butadiene exposure based on animal studies.

Administration, Inhalation↗

PubMed2003

Probabilistic framework for the estimation of the adult and child toxicokinetic intraspecies uncertainty factors.

Human health risk assessments use point values to develop risk estimates and thus impart a deterministic character to risk, which, by definition, is a probability phenomenon. The risk estimates are calculated based on individuals and then, using uncertainty factors (UFs), are extrapolated to the population that is characterized by variability. Regulatory agencies have recommended the quantification of the impact of variability in risk assessments through the application of probabilistic methods. In the present study, a framework that deals with the quantitative analysis of uncertainty (U) and variability (V) in target tissue dose in the population was developed by applying probabilistic analysis to physiologically-based toxicokinetic models. The mechanistic parameters that determine kinetics were described with probability density functions (PDFs). Since each PDF depicts the frequency of occurrence of all expected values of each parameter in the population, the combined effects of multiple sources of U/V were accounted for in the estimated distribution of tissue dose in the population, and a unified (adult and child) intraspecies toxicokinetic uncertainty factor UFH-TK was determined. The results show that the proposed framework accounts effectively for U/V in population toxicokinetics. The ratio of the 95th percentile to the 50th percentile of the annual average concentration of the chemical at the target tissue organ (i.e., the UFH-TK) varies with age. The ratio is equivalent to a unified intraspecies toxicokinetic UF, and it is one of the UFs by which the NOAEL can be divided to obtain the RfC/RfD. The 10-fold intraspecies UF is intended to account for uncertainty and variability in toxicokinetics (3.2x) and toxicodynamics (3.2x). This article deals exclusively with toxicokinetic component of UF. The framework provides an alternative to the default methodology and is advantageous in that the evaluation of toxicokinetic variability is based on the distribution of the effective target tissue dose, rather than applied dose. It allows for the replacement of the default adult and children intraspecies UF with toxicokinetic data-derived values and provides accurate chemical-specific estimates for their magnitude. It shows that proper application of probability and toxicokinetic theories can reduce uncertainties when establishing exposure limits for specific compounds and provide better assurance that established limits are adequately protective. It contributes to the development of a probabilistic noncancer risk assessment framework and will ultimately lead to the unification of cancer and noncancer risk assessment methodologies.

Adolescent↗

PubMedDate not supplied

Ancillary approaches to toxicokinetic evaluations.

The principal objective of toxicokinetic studies is to assess systemic exposure of the toxicity species to test compound during nonclinical toxicity studies by generation of pharmacokinetic data on the rate, extent, and duration of exposure. Toxicokinetics are normally integrated within the toxicity studies (concomitant); however, there are a number of circumstances when prospective, retrospective, or other ancillary types of toxicokinetic studies are performed in support of toxicity studies. The need for retrospective toxicokinetic studies arises when the original toxicity study was conducted with insufficient plasma concentration determinations, especially when pilot toxicity studies show lack of toxicity or unusual organ toxicities. Examples of ancillary toxicokinetic studies from the Drug Metabolism and Drug Safety departments at The R. W. Johnson Pharmaceutical Research Institute and from the scientific literature are provided that highlight the challenges associated with these alternate approaches. Each example includes a discussion of the rationale for the supportive toxicokinetic study, the specific experimental designs, the data interpretation, and the usefulness of the toxicokinetic data in decision-making. The ancillary toxicokinetic studies cited provided important information on establishing systemic exposure during long-term toxicity studies, allowing comparisons to human exposures, elucidating compound-related toxicities, and explaining lack of toxicity due to autoinduction and resulting low levels of parent compound.

Animals↗

PubMed2001

Providing toxicokinetic support for reproductive toxicology studies in pharmaceutical development.

A package of toxicokinetic and disposition studies is generally conducted in support of reproductive toxicology studies in the development of new drugs. The content of the package often varies between companies and sometimes either insufficient data or inappropriate/over-interpreted data are presented. This paper was written to aid investigators in the design of toxicokinetic and disposition studies in support of reproductive toxicology. It offers: (1) an overview on the regulatory guidelines for toxicokinetics, (2) methods for the derivation of toxicokinetic parameters, (3) suggestions on general toxicokinetic study design, (4) suggestions on the specific design of toxicokinetic support for reproductive toxicology studies, and (5) an overview of species differences in placental transfer and the applicability (or otherwise) of transfer studies in drug development. Toxicokinetic and drug disposition studies should be carefully designed in order to gather relevant information, and consideration should be given to the usefulness of any data before embarking on a series of supporting or routine experiments.

Animals↗

PubMedDate not supplied

Contribution of toxicokinetic modeling to the adjustment of exposure limits to unusual work schedules.

This study compared two toxicokinetic approaches for determining correction factors to be applied to occupational exposure limits (ELs) for unusual exposure scenarios: a classic one-compartment toxicokinetic approach and the physiologically based toxicokinetic (PBTK) approach. The approaches were applied to three typical unusual exposure scenarios: four consecutive 10-hour workdays followed by 3 days of recovery; three consecutive 12-hour workdays followed by 4 days of recovery; and a 4/3 work schedule. Results indicate that use of an adjustment method for ELs based on contaminant toxicokinetics generates less protective correction factors (i.e., a smaller adjustment) than those obtained using the U.S. Occupational Safety and Health Administration approach, which is based on Haber's law. Among all scenarios tested, the highest adjustment required, resulting from the use of a toxicokinetic approach (PBTK or one-compartment), was for the 4/3 work schedule and for a contaminant with a half-life equal to 18 hours. In that case the ELs would need to be reduced by 26%. Based on previous work, the authors believe an adjustment based on a toxicokinetic approach is more realistic from a toxicological standpoint. Given the value of a substance's half-life, the use of the graphs of Hickey and Reist (developed from a one-compartment toxicokinetic model) is a rapid and reliable means of establishing the correction factor. However, this approach is limited to simple and repetitive scenarios. For more complex exposure scenarios, such as that corresponding to a 4/3 work schedule, a one-compartment model also can be developed for each of the needs. Finally, the use of PBTK models allows greater flexibility for adjusting ELs for novel work schedules.

Half-Life↗

PubMedDate not supplied

New directions in the toxicokinetics of human lead exposure.

An important determinant of body lead (Pb) burden and Pb toxicity in exposed humans is Pb metabolism, or more correctly, Pb toxicokinetics. It affects the former through the quantitative processes of uptake, distribution and retention/excretion and the latter via delivery of toxic doses to cellular/molecular sites of action. Pb toxicokinetics has useful application in understanding Pb's behavior in populations. Several of these applications have been studied and results are presented for the toxicokinetic basis of dose-neurotoxic effect relationships in selected longitudinal studies and the use of toxicokinetic modeling for estimation of body lead burden in early populations. Three well-known, ongoing longitudinal studies of developmental neurotoxicity--in Boston, Cincinnati, and Port Pirie, Australia--involve cohorts who differ markedly as to their pre- and postnatal lead exposure profiles. Toxicokinetic examination of these exposure differences helps to explain the temporal variability seen in blood Pb-toxic effect relationships and supports a causal role for lead. Toxicokinetic models of Pb uptake and in-vivo behavior are increasingly being considered for estimating Pb-B levels in lieu of direct measurement. A linear biokinetic model, using reliable input data for natural/prehistoric levels of Pb in sources, was applied to estimation of prehistoric/preindustrial children's blood lead. A range of 0.06 to 0.12 microgram/dl was estimated for two lead intakes. These estimates are still two orders of magnitude (85 to 165-fold) lower than the newly issued CDC toxicity guideline for children of 10 micrograms/dl. Lastly, the toxicokinetics of lead in bone, particularly its resorption with metabolic stimuli, is of concern, particularly for "baby boom" women who are either of childbearing age or approaching menopause and who had greatly elevated environmental lead exposures in the 1940s to 1970s.

Developing Countries↗

PubMed2003

Toxicokinetics of the nerve agent (+/-)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration.

In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(+/-)P(+/-)-soman and (+/-)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (+/-)-VX. A validated method was developed to determine blood levels of (+/-)-VX by means of achiral gas chromatography at blood levels > or =10 pg/ml. The ratio of the two enantiomers of VX in blood could be measured at levels > or =1 ng/ml by using chiral HPLC in combination with off-line gas chromatographic analysis. In order to obtain basic information on the toxicokinetics of (+/-)-VX, i.e., under conditions of 100% bioavailability, the blood levels of this agent were measured in hairless guinea pigs at iv doses corresponding with 1 and 2 LD50. The derived AUCs indicate a reasonable linearity of the toxicokinetics with dose. Also, the toxicokinetics in marmoset primates was studied at an absolute iv dose corresponding with 1 LD50 in the hairless guinea pig which led to approximately the same levels of (+/-)-VX in blood as observed at 2 LD50 in the hairless guinea pig. Finally, the toxicokinetics of (+/-)-VX were measured in hairless guinea pigs via the most relevant porte d' entrée for this agent, which is the percutaneous route at a dose corresponding with 1 LD50 (pc). Large variations were observed between individual animals in the rate of penetration of (+/-)-VX and in concomitant progression of AChE inhibition in blood of these animals. Blood levels of (+/-)-VX increased gradually over a 6-h period of time. After a 7-h penetration period, the total AUC corresponded with 2.5% bioavailability relative to iv administration. In contrast with the G-agents C(+/-)P(+/-)-soman and (+/-)-sarin, stereospecificity in the sequestration of the two enantiomers of (+/-)-VX is not a prominent phenomenon. It appears that (+/-)-VX is substantially more persistent in vivo than the two G-agents. This persistence may undermine the efficacy of pretreatment with carbamates of percutaneous intoxication in particular due to gradual replacement of carbamate on AChE by (+/-)-VX, whereas classical treatment of intoxication with oximes is hampered by the short persistence of oximes relative to the agent.

Acetylcholinesterase↗

PubMedDate not supplied

The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment.

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal's fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics.

Biotransformation↗

PubMed2006

Toxicokinetics of inhaled trichloroethylene and tetrachloroethylene in humans at 1 ppm: empirical results and comparisons with previous studies.

Trichloroethylene (TRI) and tetrachloroethylene (TETRA) are solvents that have been widely used in a variety of industries, and both are widespread environmental contaminants. In order to provide a better basis for understanding their toxicokinetics at environmental exposures, seven human volunteers were exposed by inhalation to 1 ppm of TRI or TETRA for 6 h, with biological samples collected for analysis during exposure and up to 6-days postexposure. Concentrations of TRI, TETRA, free trichloroethanol (TCOH), total TCOH (free TCOH plus glucuronidated TCOH), and trichloroacetic acid (TCA) were determined in blood and urine; TRI and TETRA concentrations were measured in alveolar breath. Toxicokinetic time courses and empirical analyses of classical toxicokinetic parameters were compared with those reported in previous human volunteer studies, most of which involved exposures that were at least 10-fold higher. Qualitatively, TRI and TETRA toxicokinetics were consistent with previous human studies. Quantitatively, alveolar retention and clearance by exhalation were similar to those found previously but blood and urine data suggest a number of possible toxicokinetic differences. For TRI, data from the current study support lower apparent blood-air partition coefficients, greater apparent metabolic clearance, less TCA production, and greater glucuronidation of TCOH as compared to previous studies. For TETRA, the current data suggest TCA formation that is similar or slightly lower than that of previous studies. Variability and uncertainty in empirical estimates of total TETRA metabolism are substantial, with confidence intervals among different studies substantially overlapping. Relative contributions to observed differences from concentration-dependent toxicokinetics and interindividual and interoccasion variability remain to be determined.

Air Pollutants↗

PubMedDate not supplied

Differences between pharmacokinetics and toxicokinetics.

Pharmacokinetics has evolved into a highly interactive discipline in which the dispositional characteristics of an administered drug are often compared to the time course of observed drug effects. The more recent discipline of toxicokinetics is undergoing a similar, although belated, evolution. While toxicokinetic studies were first intended to demonstrate merely that toxicology test animals received drug, they now provide a critical evaluation of drug disposition at toxicologic doses and also the relationships between toxicokinetic values and the occurrence and time course of toxic events. Different dose levels used in toxicokinetics, compared to pharmacokinetics, give rise to technological changes in such factors as solubility, stability, absorption, presystemic clearance, protein binding, and metabolism that may be influenced by dose size, and may give rise to profound differences in the design and interpretation of studies. Pharmacokinetic and toxicokinetic studies also have different objectives. While preclinical pharmacokinetic and pharmacodynamic studies provide correlates, based on generally well-established parameters, that may provide useful but perhaps not essential information to guide drug dosage in man, information from toxicokinetics and toxicodynamic studies, which is difficult to obtain because of capricious interspecies differences in dispositional characteristics and organ/tissue sensitivities, is critical to predict the behavior and safety of compounds in man.

Drug-Related Side Effects and Adverse Reactions↗

PubMed1989

Effect of a metal mixture in diet on the toxicokinetics and toxicity of cadmium, mercury and manganese in rats.

The purpose of this work was to determine whether a metal mixture added to diet influences the toxicokinetics and toxicity of some elements. The metal mixture (MM) used in these experiments was ash (slag) from a coal gasification plant. The effect of this mixture (5 percent in diet) on the toxicokinetic and on the acute or subchronic toxicity of Cd, Hg, Mn was determined in rats of different ages. Rats were exposed for five weeks in toxicokinetic and six weeks in acute toxicity experiments. Sucklings were exposed through their mothers, which received the MM in diet over the pregnancy and lactation period. In toxicokinetic studies, half of the animals additionally received Cd, Hg or Mn (100, 50 or 2000 ppm, respectively) in drinking water. In subchronic experiments, six-week-old albino rats of both sexes were given MM in the diet and Cd, Hg or Mn in drinking water for 16 weeks. In toxicokinetic studies, 115mCd, 203Hg or 54Mn were administered orally or intraperitoneally to mothers and pups. Exposure to MM had no effect on the absorption, retention and organ distribution of these elements determined six days after radioisotope administration. In acute toxicity studies, exposure to MM in diet had no effect on LD50 values obtained eight days after oral administration of Cd, Hg or Mn to rats of different ages. In subchronic experiments, the effect of individual metals (Cd, Hg or Mn) was similar in animals with and without simultaneous exposure to the metal mixture (only a slight potentiation of a few health-effect parameters of cadmium was noticed in some animals). It is concluded that oral exposure to MM in the diet had almost no effect on the toxicokinetics and toxicity of Cd, Hg and Mn. This could be explained by the low level or low bioavailability of elements from MM, by the metal-metal interaction within the mixture or by the choice of health effect indicators determined. These results are presented as one of the potential approaches for studying the health effect of a metal mixture as occurring in the environment.

Aging↗

PubMed2004

Incorporating children's toxicokinetics into a risk framework.

Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper.

Adult↗

PubMed1994

The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity.

This article reviews the present state of the art regarding the toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). The absorption, body distribution, and metabolism can vary greatly between species and also may depend on the congener and dose. In biota, the 2,3,7,8-substituted PCDDs and PCDFs are almost exclusively retained in all tissue types, preferably liver and fat. This selective tissue retention and bioaccumulation are caused by a reduced rate of biotransformation and subsequent elimination of congeners with chlorine substitution at the 2,3,7, and 8 positions. 2,3,7,8-Substituted PCDDs and PCDFs also have the greatest toxic and biological activity and affinity for the cytosolic arylhydrocarbon (Ah)-receptor protein. The parent compound is the causal agent for Ah-receptor-mediated toxic and biological effects, with metabolism and subsequent elimination of 2,3,7,8- substituted congeners representing a detoxification process. Congener-specific affinity of PCDDs and PCDFs for the Ah-receptor, the genetic events following receptor binding, and toxicokinetics are factors that contribute to the relative in vivo potency of an individual PCDD or PCDF in a given species. Limited human data indicate that marked species differences exist in the toxicokinetics of these compounds. Thus, human risk assessment for PCDDs and PCDFs needs to consider species-, congener-, and dose-specific toxicokinetic data. In addition, exposure to complex mixtures, including PCBs, has the potential to alter the toxicokinetics of individual compounds. These alterations in toxicokinetics may be involved in some of the nonadditive toxic or biological effects that are observed after exposure to mixtures of PCDDs or PCDFs with PCBs.

Animals↗