Toxicokinetics dose-response relationships

Pentachlorophenol is an effective broad-spectrum biocide widely used as a wood preservative. Two-year carcinogenicity studies had been conducted in B6C3F1 mice and similar studies were planned in Fischer 344 rats. To aid in future comparison of the results of the toxicology studies in both species and to provide information for dose-response relationships, toxicokinetic evaluations were conducted. In singlc-and multiple-exposure studies the toxicokinetics of... 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

Further data on the effects of chronic inhalation exposure to 1,4-dichlorobenzene would be useful, especially because chronic exposures to 1,4-dichlorobenzene in the air, in the home, and the workplace are the main sources of human exposure to this chemical. Any further testing of the effects of chronic exposure to 1,4-dichlorobenzene via the oral route should probably be done at lower levels of 1,4-dichlorobenzene than those that have already been used in the NTP (1987) bioassay, and should focus on dose-response relationships involving the hepatic, renal, hematopoietic, central nervous system, and metabolic pathways. Data on the effects of chronic dermal exposure to 1,4-dichlorobenzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated from toxicokinetic studies, since chronic dermal exposure to 1,4-dichlorobenzene occurs as a result of bathing and showering in drinking water that contains low levels of this chemical in many U.S. communities. 

Currently, most risk assessments on environmental chemicals use dose-response relationships based on potential dose or internal dose, since the toxicokinetics necessary to base relationships on... 

Integration of toxicokinetic investigations into the reproductive studies is encouraged to better evaluate dose-response relationships, although this is not a mandatory requirement. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

In characterizing the database, a number of assumptions are applied when data are not available or are incomplete (USEPA, 1991 IPCS, 2005 Kimmel et al., 2006). These include uncertainties about toxicokinetics, mechanism of action, low-dose-response relationships, and human exposure patterns. Each of these assumptions is supported to some extent by the scientific literature. The following assumptions are generally accepted in risk assessment strategies ... 

Based in this information difference between the NOEL and human exposure or the risk at a given exposure is determined. Humans may be exposed to chemicals in the air, water, food, or on the skin. From the concentrations of a chemical in these different compartments the external daily exposure is estimated. The response to the chemical depends upon duration and route of exposure, the toxicokinetics of the chemical, the dose-response relationship and the susceptibility of the individual. Thus, the precise definition of the terms hazard, exposure, and risk is essential to understand toxicological evaluations (details on data requirements and procedures for risk assessment are given subsequently). 

Methylarsines (mono-, di- and trimethylarsine) are strong irritants, but these compounds are less powerful than arsine as hemolytic agents. No quantitative data on the toxicokinetics and dose-response relationships for the methylarsines were located. ... 

The fundamental principle of toxicology is the concept that the sixteenth century physician Paracelsus articulated in the 1500s sola dosis facit venenum or the dose makes the poison . The modem version of this observation is the dose-response relationship, which is experimentally and theoretically supported through pharmacokinetic and pharmacodynamic experimentation. Pharmacokinetics is concerned with the study of the time course of the disposition of drugs, specifically absorption, distribution, metabolism and elimination, often referred to as ADME. In non-technical terms it can be thought of as what the body does to the chemical. An understanding of the pharmacokinetic (in the case of dmgs) or toxicokinetic (all chemicals) profile is critical to estimate the... 

See also Dose-Response Relationship Food and Drug Administration, US Investigative New Drug Application LD50/LC50 (Lethal Dosage 50/Lethal Concentration 50) Pharmacokinetics/Toxicokinetics Redbook. 

As described in a highly referenced document (NRC, 1983), important components of this process include hazard identification, assessment of exposure and dose-response relationships, and characterization of the risk. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans (i.e. interspecies variation in toxicokinetics), and extrapolation from high-dose to low-dose exposures. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. 

Hazard characterization consists of qualitative or quantitative evaluation of the adverse health effects associated with different agents, whether they are chemicals or microorganisms. This step comprises several elements, like toxicokinetics (absorption, distribution, metabolism, and excretion of the toxic agent), mechanism of toxic action, dose-response relationships, target organs and different end points, like acute or chronic toxicity, teratogenicity, neoplastic manifestations, and so forth. 

Second, lead s kinetic behavior in vivo provides the means by which one can identify and exploit biomarkers of toxic lead exposures as well as determine the dose portion of critical dose—toxic response relationships for lead poisoning. Measurement of lead in whole blood and its relatively reliable use in determining both systemic lead exposure and the extent of toxic injury (dose—response relationships) is mainly feasible because we understand how Pb s toxicokinetic behavior in blood relates to the temporal and toxicological... 

PbP is a relatively rapid reflection of Pb uptake and distribution toxicokinetics in human populations (NAS/NRC, 1993 U.S. EPA, 2006) and is the in vivo medium by which Pb is excreted to urine through glomerular filtration in humans. This behavior in terms of rapid exchange of Pb with target tissues and PbP makes the latter a more temporally sensitive biomarker for toxicokinetics and toxicodynamics. Little has evolved in the more current toxicological literature on Pb to quantify dose—response relationships using PbP as the dose metric beyond attempts at elucidating the exposure marker trio of PbB, PbP, and Pb in bone. 

A critical question in fetal Pb toxicokinetics is how one best measures dose—response relationships among various exposure biomarkers as well as relationships governing dose—toxic response relationships. It is now accepted that bone Pb is a better biomarker in constmcting dose—toxic response relationships for a variety of toxic effects than are indicators such as PbB. This was demonstrated in Chapter 13 describing cardiovascular effects of Pb. 

As noted earlier, plasma Pb, although the more precise and meaningful toxicokinetic measure for interorgan Pb distribution and eventual dose—response relationships, has a myriad of analytical problems associated with its measurement (Mushak, 1998 U.S. EPA, 2006). For example, plasma lead content even in high exposures is quite low, so that contaminating Pb because of external contamination or Pb passage from hemolyzed cells to... 

Part 2 and its chapters presented the topic of human lead exposure in global and categorical terms, addressing the technical areas of lead intakes, uptakes (absorption), toxicokinetics, integration of toxicokinetics into in vivo disposition in a manner allowing quantitative assessments of lead exposure, etc. In contrast to these broadly descriptive aspects of human Pb exposme, the applied health discipline of quantitative risk assessment requires prescriptive approaches for site-specific, case-specific, and environmental scenario-specific lead exposure characterizations. Data from such specific exposure characterizations are combined with available data for lead dose—response relationships to arrive at some quantitative risk characterization indexed as some endpoint for human health risk. 

It is difficult to establish uniform guidelines for pharmacokinetic studies for biotechnology-derived pharmaceuticals. Single and multiple dose pharmacokinetics, toxicokinetics, and tissue distribution studies in relevant species are useful however, routine studies that attempt to assess mass balance are not useful. Differences in pharmacokinetics among animal species may have a significant impact on the predictiveness of animal studies or on the assessment of dose response relationships in toxicity studies. Alterations in the pharmacokinetic profile due to immune-mediated clearance mechanisms may affect the kinetic profiles and the interpretation of the toxicity data. For some products there may also be inherent, significant delays in the expression of pharmacodynamic effects relative to the pharmacokinetic profile (e.g., cytokines) or there may be prolonged expression of pharmacodynamic effects relative to plasma levels. 

The complexity of toxicokinetic processes of solvents can be described in models, e.g., predicting exposure situations and distribution phenomena in the human body and quantifying these processes (e.g. dose-effect response relationships). This applies especially to Simula-... 

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