Toxicokinetics lead distribution

For convenience, the processes identified in Figure 2.1 can be separated into two distinct categories toxicokinetics and toxicodynamics. Toxicokinetics covers uptake, distribution, metabolism, and excretion processes that determine how much of the toxic form of the chemical (parent compound or active metabolite) will reach the site of action. Toxicodynamics is concerned with the interaction with the sites of action, leading to the expression of toxic effects. The interplay of the processes of toxicokinetics and toxicodynamics determines toxicity. The more the toxic form of the chemical that reaches the site of action, and the greater the sensitivity of the site of action to the chemical, the more toxic it will be. In the following text, toxicokinetics and toxicodynamics will be dealt with separately. 

Absorption, Distribution, Metabolism, Excretion. Examination of Section 2.6 clearly indicates that oral administration of NDMA has been the preferred route for studying its absorption, distribution, metabolism and excretion. This is not surprising since oral administration is easier to monitor when compared to other routes. The oral route seems to be the most pertinent to study since humans are most likely to be exposed to nitrosamines orally. Toxicokinetic data with regard to dermal and inhalation exposure of NDMA are clearly lacking. Furthermore, dermal and inhalation exposures may lead to different metabolic pathways and patterns of distribution and excretion, which could account for differences in the degree of toxicity exhibited by different routes of exposure. The metabolism of NDMA in isolated microsomal preparations seems to be well understood, but studies with cultured human cells could provide additional useful information. However, exploration of the denitrosation mechanism as an alternative to a-hydroxylation requires more attention. Determination of the urinary excretion of NDMA in control human volunteers and in individuals known to consume foods with high contents of nitrosamines could provide information concerning absorption and excretion of the xenobiotic. 

The toxicokinetics of toluene have been well characterized in laboratory animals (Benignus et al. 1981 Benignus 1982). In rats, after inhalation exposure, toluene was quickly absorbed and distributed in lipoidal and highly vascularized tissues. Within an hour of inhalation exposure at 2,167 mg/m3, about 95% of maximal concentrations in blood and brain were achieved. Toluene is metabolized principally by series of oxidation reactions that lead to benzoic acid, which is conjugated with glycine to form hippuric acid. Unchanged toluene is readily removed in exhaled air. 

The toxicokinetics of lead— that is, its absorption, distribution, metabolism, and excretion— and its relevance to common biomaikers of exposure are schematically represented in Figure 3-1. 

Chapter 7 presents the levels of lead intakes in various subsets of affected human populations. The term intake as employed in the book describes amounts of media-specific Pb inhaled or ingested per unit time, typically daily, that enter the chief receiving body compartments the gastrointestinal (GI) and respiratory tracts. Chapter 8 describes the biokinetics of Pb, specifically the toxicokinetics of Pb in human populations and the toxicokinetic basis of lead exposure biomarkers. It deals with the absorption (uptake) rate of Pb, subsequent distribution of the element into the body post-uptake, the rate of retention over the short and long term, and the rate of short- or long-term excretion of the substance. 

Absorbed lead is distributed first to blood and then to diverse body compartments in humans and experimental animals. Entry into and movement out of subcompartments of blood are closely linked with the toxicokinetic correlates of toxic lead exposures and associated lead poisoning. 

SubceUular distribution of Pb in human soft tissues appears to mainly involve the mitochondria and nuclei, two organelles known to either be affected toxicologically by lead or be involved in Pb sequestration and toxicokinetics. Intranuclear inclusion bodies, for example, have long been known to form as a transitory protective mechanism for averting or delaying lead toxicity. Lead in relatively large amounts is sequestered in nuclear inclusions and the biochemical and structural characteristics of these bodies have been described (Carroll et al., 1970 Moore et al., 1973). Cramer et al. (1974) showed the formation of intranuclear inclusions as an early response to Pb in kidney proximal tubule cells in new lead workers. 

Mineralizing tissue in humans consists of bone and teeth. These biominerals differ in a number of ways with respect to lead deposition and lead toxicokinetics. By and large, bone is the larger repository of lead in humans and is the more complex mineralizing tissue in terms of deposited Pb. Bone Pb can be readily resorbed and serve as a source of endogenous Pb exposure long after initial transport to and deposition in the various bone subcompartments. Table 8.9 presents illustrative summaries of Pb distributions and accumulations in human mineralizing tissues. 

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... 

Such exposure events that lead to poison uptake and its distribution in an organism are part of the invasion process, whereas all steps causing a decrease in poison (e.g., elimination by degradation, biotransformation, and excretion) are part of the evasion process. For a better understanding of the pathophysiology and toxicokinetics of CWAs, an overview of the routes of poison incorporation is given in the next section, with a special emphasis on OP nerve agents and vesicants. 

Ageing-associated events may alter toxicokinetics, as determined in a recent cross-sectional study from our laboratory (Cory-Slechta, in preparation). Groups of young (weanling), adult (8 months of age) and old rats (16 months of age) were exposed to 50 ppm lead acetate in drinking water for 8 months. Subsequent tissue lead determinations revealed an age-related shift in the distribution of lead, with a pronounced increase with age in both brain (Figure 2) and liver, but not in kidney. This effect may have resulted from the release... 

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