EVALUATION AND MODIFICATION OF A PHYSIOLOGICALLY-BASED MODEL OF LEAD KINETICS USING DATA FROM A SEQUENTIAL ISOTOPE STUDY IN CYNOMOLGUS MONKEYS

Endogenous (predominantly bone) and exogenous lead were differentially labeled in two 11-year-old female cynomolgus monkeys (Macaca fascicul aris) to establish the contributions of the two sources to blood lead, The monkeys had been administered a common lead isotope ''mix'' at th e rate of about 1300 mu g Pb/kg body wt/day from age 10 months until t he start of the study, On day 0, common lead was replaced in sequence by mixes artificially enriched in Pb-204, Pb-206, and Pb-207, given fo r periods of from 50 to 281 days. Total lead ingestion rate was held c onstant except during administration of the Pb-207-enriched mix to one of the monkeys, when it was reduced to 650 mu g/kg/day. Blood and bon e were sampled at intervals and analyzed for their content of each of the isotope mixes, A physiologically based model of human lead kinetic s was scaled to the cynomolgus monkey and fit to the data to test the correctness of the model structure and to assist with interpretation o f study results, Fractional absorption was varied to achieve the best visual fits of the scaled model to blood and bone concentration data f or each monkey, The model failed to reproduce the sharp drop in isotop e concentrations in blood observed after each exchange of isotope mix, Consequently, it was revised to include a rapid-turnover trabecular b one compartment and a slow-turnover cortical bone compartment, using e stimates of trabecular and cortical bone turnover rates from histomorp hometric studies in adult cynomolgus monkeys. The revised model fit mo st of the sets of bone and blood concentrations well, About 17% of the blood lead originated from bone after 11 years of exposure, at blood lead concentrations in excess of 50 mu g/dl. The rate of return of com mon lead from bone, as estimated from the model, was 28 mu g/day just before termination of controlled common lead exposure on day 0, Based on the success of the scaled human model in fitting these data and on the absolute and relative values of bone and blood lead concentrations , the metabolism of lead in the cynomolgus monkey appears to be simila r to human lead metabolism. (C) 1998 Academic Press.