Review and Evaluation of the Potential Impact of Age- and Gender-Specific Pharmacokinetic Differences on Tissue Dosimetry

Abstract

In standard risk assessment methods for carcinogenic or noncarcinogenic chemicals, quantitative methods for evaluating interindividual variability are not explicitly considered. These differences are currently considered by the use of statistical confidence limits or default uncertainty factors. This investigation consisted of multiple tasks aimed at making quantitative predictions of interindividual differences in susceptibility by using physiologically based pharmacokinetic (PBPK) models. Initially, a systematic, comprehensive review of the literature was conducted to identify any quantitative information related to gender- or age-specific physiological and biochemical factors that could influence susceptibility to chemical exposure. These data were then organized from a pharmacokinetic perspective by process and by chemical class to identify key factors likely to have a significant impact on susceptibility as it relates to internal target tissue dose. Overall, a large number of age- and gender-specific quantitative differences in pharmacokinetic parameters were identified. The majority of these differences were identified between neonates/children and adults, with fewer differences identified between young adults and the elderly. The next phase of this work consists of using PBPK models to develop examples of approaches through the development of case studies. The goal of the case studies is to continue to develop a methodology that incorporates PBPK modeling to assess the likelihood that a chemical or class of chemicals may present an age- or gender-specific risk. The case studies should also demonstrate practical methods for quantitatively incorporating information on age- and gender-specific pharmacokinetic differences in risk assessments for chemicals.

Regional Deposition of Submicrometer Aerosol in the Human Respiratory System Determined at 1-s Time Resolution of Particle Size Distribution Measurements

“…This value in the adult lung varies from 200 to 600 million. At birth, the alveolar surface area is approximately 3 m 2 ; while in adults, the alveolar surface area is 75 m 2 (Clewell et al, 2002). Considering such values of alveolar surface area, Fig.…”

Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling

“…Volatile compounds like the THMs are eliminated from the body rapidly after the exposure ceases and hence the biomarker concentrations are highly sensitive to recent exposures. Recent exposure is of less concern for highly persistent compounds like dioxin, but the biomarker concentrations in this case could be affected by physiological changes such as growth or altered body fat content (Clewell et al, 2004). These considerations need to be explicitly characterized and quantified before it will be possible to interpret biomonitoring data for these compounds.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…Ginsberg et al (2005) indicated that the particle dose in the pulmonary region is also likely to be two to four times higher in three-month-old children than in adults, particularly for submicrometre-size particles. The skin surface area relative to body weight is greater in children than in adults, such that the potential dose received following dermal exposure is likely to be about three times greater in infants than in adults (Clewell et al, 2002). The permeability of the epidermal barrier is poorly developed in the preterm infant, resulting in greater percutaneous absorption of chemical agents.…”

“…bromosulfthalein, bilirubin), for example, are longer in newborns than in adults. Renal clearance has been shown to be lower in neonates than in older children and adults, for all chemical classes: lipophilic, hydrophilic, and organic ions (Clewell et al, 2002). Glomerular filtration rate at normal-term birth is about one third of the adult value when expressed on the basis of body surface area and matures in about six months.…”

“…A systematic comparison of the available information on agedependent maturation of metabolic and elimination processes as well as the toxicokinetics of chemicals in developing neonatal and young animals with that in infants and children can be found elsewhere (Gladtke, 1973;Stewart & Hampton, 1987;Crom, 1994;Renwick, 1998;Clewell et al, 2002;Alcorn & McNamara, 2003;Kearns et summarizes the age dependency of toxicokinetic processes and determinants in children compared with adults.…”