Standards for exposure to lead in workplace air and in ambient air are based on the relationship between lead in air and lead in blood. However, there is controversy as to whether lead in blood represents biologically active lead and, indeed, whether the two are linearly related. Thus, there is need for a reliable model of lead kinetics that incorporates effect measurements and, at the same time, facilitates interspecies conversion of lead exposure and effect data. Without exception, all of the models of lead kinetics proposed to date have no predictive power across age or species, nor do they take into account the possibility that effective lead dose is not proportional to blood lead. The purposes of this proposal are to develop a physiological toxicokinetic model of the behavior of lead and to incorporate into the model the relationships between the magnitudes of selected promptly-occurring effects of lead and plasma lead, the most promising index of biologically active lead. The physiological toxicokinetic model will be developed for the rat. Its predictive accuracy will be challenged by scaling it up to the rabbit and the human, and examining its performance against blood and tissue lead concentration data obtained from complementary experimental studies in the rabbit and against large pre-existing blood lead data bases in humans. Correlations between the magnitudes of elevation of Delta-aminolevulinic acid and of free erythrocyte protoporphyrin in blood and plasma lead measurements will be evaluated in the rat and rabbit, and in humans to the extent to which existing data permit. The proposed physiological toxicokinetic model will be the first developed for a nonvolatile material that is not relatively rapidly metabolized and excreted, and in particular will be the first integrated physiologically-based model of lead kinetics in humans. It also will provide a framework within which the contributions of determinants of effective dose and determinants of inherent species susceptibility to species differences in acute effects of lead can be evaluated, with the potential for extension to measures of chronic toxicity. The long-term objective of this work is to develop meaningful correlations among amounts of biologically active agents, magnitudes of acute effects, and measures of chronic toxicity.
| O'Flaherty, E J (1993) Physiologically based models for bone-seeking elements. IV. Kinetics of lead disposition in humans. Toxicol Appl Pharmacol 118:16-29 |
| O'Flaherty, E J (1991) Physiologically based models for bone-seeking elements. I. Rat skeletal and bone growth. Toxicol Appl Pharmacol 111:299-312 |
| O'Flaherty, E J (1991) Physiologically based models for bone-seeking elements. III. Human skeletal and bone growth. Toxicol Appl Pharmacol 111:332-41 |
| O'Flaherty, E J (1991) Physiologically based models for bone-seeking elements. II. Kinetics of lead disposition in rats. Toxicol Appl Pharmacol 111:313-31 |
