TOXICOKINETICS OF LEAD

This chapter presents an overview of the exposure considerations for lead that are relevant to firing ranges, including an overview of the routes of exposure, factors that affect internal doses of lead, and exposure factors that influence health outcomes. 

Several terms are used differently by toxicologists and epidemiologists, so definitions are provided for terms as they are used here. Dose is the amoimt of a substance to which a person is exposed over some period. An exposure dose is how much of a substance is encoimtered in the environment. An absorbed dose or internal dose is the amount of a substance that gets into the body through the eyes, skin, stomach, intestines, or lungs. One needs to differentiate exposure (lead outside the body) from the internal dose. 

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The toxicokinetics of lead in children appears to be similar to that in adults, with the exception of the higher absorption of ingested lead in children. Most of the lead body burden in both children and adults is in bone a slightly large fraction of the body burden in adults resides in bone (Barry 1975). The difference may reflect the larger amount of trabecular bone and bone turnover during growth trabecular bone has a shorter retention halftime for lead than does cortical bone (See Section 2.3.3 for details). 

Palminger Hallen I, Jonsson S, Karlsson MO, et al. 1996. Toxicokinetics of lead in lactating and nonlactating mice. Toxicol Appl Pharmacol 136 342-347. 

At least three polymorphic genes have been identified that potentially can influence the bioaccumulation and toxicokinetics of lead in humans (1) the gene coding for 6-amino-levulinic acid dehydratase (ALAD) (2) the Vitamin D receptor (VDR) gene and (3) HFE, the gene for hereditary hemochromatosis (Onalaja et al. 2000). 

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. 

TABLE 14.9 Transplacental Transfer Toxicokinetics of Lead in Human Populations ... 

These experts collectively have knowledge of lead s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. 

The toxicokinetic and toxicological behavior of lead can be affected by interactions with essential elements and nutrients (for a review see Mushak and Crocetti 1996). In humans, the interactive behavior of lead and various nutritional factors is particularly significant for children, since this age group is not only sensitive to the effects of lead, but also experiences the greatest changes in relative nutrient status. Nutritional deficiencies are especially pronounced in children of lower socioeconomic status however, children of all socioeconomic strata can be affected. 

Mushak P. 1993. New directions in the toxicokinetics of human lead exposure. Neurotoxicology 14 29-42. 

Animal studies indicate that nutritional deficiencies in a number of essential elements (e.g., calcium, iron, zinc, copper, phosphorus) may impact the toxicokinetic and toxicological behavior of lead (ATSDR 1993 Chaney et al. 1989). In infants and children, lead retention has been shown to be inversely correlated with calcium intake (Johnson and Tenuta 1979 Sorrell et al. 1977 Ziegler et al. 1978). Zinc has been shown to have a protective effect against lead toxicity in a number of animal species (Goyer 1986 Haeger-Aronsen et al. 1976 Brewer et al. 1985 Cerklewski and Forbes 1976). 

We have studied the toxicokinetics of heavy metals (arsenic, lead, manganese and copper), as well as of organophosphorus and clorinated pesticides. It has been shown that they are all characterized by different... 

M.B. Rabinowitz, Toxicokinetics of bone lead. Environ. Health Perspect. 91 (1991) 33-37. 

When appropriately validated and understood, biomarkers present unique advantages as tools for exposure assessment (Gundert-Remy et al, 2003). Biomarkers provide indices of absorbed dose that account for all routes and integrate over a variety of sources of exposure (IPCS, 1993, 2001a). Certain biomarkers can be used to represent past exposure (e.g. lead in bone), recent exposure (e.g. arsenic in urine), and even future target tissue doses (e.g. pesticides in adipose tissue). Once absorbed dose is determined using biomarkers, the line has been crossed between external exposure and the dose metrics that reflect the pharmacokinetics and toxicokinetics of an agent (see section 5.3.3). 

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. 

Interpretation and understanding of the toxicokinetics of nerve agents would not be possible without taking into consideration that these agents consist of mixtures of stereoisomers, which are often extremely different in their toxicokinetic and toxico-dynamic properties. A common feature of these agents is the presence of chirality (asymmetry) around the phosphorus atom. Therefore, O-isopropyl methylphos-phonofluoridate (sarin) and 0-ethyl S-(2-diisopropylaminoethyl) methylphospho-nothioate (VX) consist of equal amounts of stereoisomers, denoted as (-1-)- and (-)-sarin and (-1 )- and (-)-VX, respectively. In the case of 0-1,2,2-trimethylpropyl methylphosphonofluoridate (soman), an additional chiral center resides in the 1,2,2-methylpropyl (pinacolyl) moiety, leading to the presence of four stereoisomers. Synthetic soman, i.e., a mixture of the four stereoisomers, is denoted as C( )P( )-soman, whereas the individual four stereoisomers are denoted as C(+)P(-l-), C(-H)P(-), C(-)P(+), and C(-)P( ), in which C stands for chirality in the pinacolyl moiety and P for chirality around phosphorus. The enantiomeric pairs [C(-r)P(+) + C(-)P( )] and [C(+)P(-) -l- C(-)P(+)] are present in synthetic... 

To determine the toxicokinetic behavior of lead (especially lead in bone). 

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. 

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