The net effect of the aforementioned factors on pesticide absorption in the immature individual is hard to predict because they sometimes oppose one another, change at different rates in the maturing organism, and often are ill-defined in humans.

Distribution and Uptake of Chemicals

Distribution of a chemical to sites of action in different tissues, following systemic absorption, is governed by a number of factors. These include plasma protein binding, extracellular fluid volume, adipose tissue mass, organ blood flow, tissue uptake, and tissue binding. The factors exert their influence concurrently and may compete with one another. They may change to varying degrees at different rates during postnatal development. Thus, the net effect of maturation on the quantity of a particular chemical reaching a target tissue is difficult to ascertain. There are few data on binding and distribution of pesticides in infants and children, but a variety of drugs have been relatively well studied (Kearns and Reed, 1989). These are used to illustrate how chemical distribution and uptake can vary with age in the developing individual.

Protein Binding Numerous chemicals, including a variety of pesticides, bind reversibly to plasma proteins. As long as the compounds are bound, they are not able to leave the bloodstream and reach sites of action (i.e., produce biological effects) in extravascular tissues. Although increased plasma protein binding thereby generally reduces the maximum bioactivity of chemicals, binding can prolong their effects by slowly releasing them to sites of action as well as to sites of inactivation or elimination. Much of our current knowledge of how altered plasma protein binding affects the health of infants and children has been gained from clinical studies of therapeutic agents.

Many drugs exhibit significantly lower plasma protein binding in premature and full-term newborns than in adults (Table 3-3). Investigators typically take blood samples from the umbilical cord at the time of delivery and determine the percentage of free, or unbound, drug in the sample. A diverse group of therapeutic agents, including both acidic and basic compounds, exhibit considerably reduced plasma protein binding in perinatal subjects (Morselli et al., 1980; Morselli, 1989). This group includes such common drugs as phenobarbital, digoxin, theophylline, phenytoin, lidocaine, imipramine, and diazepam. Though data for certain age groups are lacking for a number of these drugs, it appears that the age at which binding reaches adult levels is compound-specific. Rane et al. (1971), in a comprehensive study of the age-dependency of the plasma protein binding of phenytoin (a weak acid), found that adult values were approached in infants and young children 3 months to 2 years old. The



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