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A physiologically based pharmacokinetic (PBPK) model for human pregnancy must incorporate many factors that are not usually encountered in PBPK models of mature animals. Models for pregnancy must include the large changes that take place in the mother, the placenta and the embryo/fetus over the period of pregnancy. The embryo/fetal weight change was modeled using the Gompertz equation for growth which gave a good fit to extensive pooled weight data of the human embryo/fetus from 25 to 300 days of gestation. This equation is based on a growth rate that is proportional to the total weight of the organism with the proportionality factor decreasing exponentially with time. Allometric equations, which are widely used to relate organ weights, blood flow rates and other attributes of mature animals to total weight, were adapted to correlate fetal organ weights with total fetal weight. Allometric relationships were also developed for plasma flow rates and other organ-related parameters. The computer model, written in FORTRAN 77, included 27 compartments for the mother and 16 for the fetus; it also accommodates two substances allowing representation of a parent compound and a metabolite (or a second drug or environmental substance). Although this model is large, the inherent sparsity in the equations allow it to be solved numerically in a reasonable time on currently available, reasonably priced desktop computers. A nonlinear regression routine is included to fit key model parameters to experimental data. Concentrations of chemicals administered and measured in the mother may be simulated in both maternal and fetal organs at any day(s) between 25 days and 300 days of gestation. Allometric relationships are also utilized to adopt this human model for use with data obtained from animal experiments.

Physiologically based pharmacokinetic (PBPK) models need the correct organ/tissue weights to match various total body weights in order to be applied to children and the obese individual. Baseline data from Reference Man for the growth of human organs (adrenals, brain, heart, kidneys, liver, lungs, pancreas, spleen, thymus, and thyroid) were augmented with autopsy data to extend the describing polynomials to include the morbidly obese individual (up to 250 kg). Additional literature data similarly extends the growth curves for blood volume, muscle, skin, and adipose tissue. Collectively these polynomials were used to calculate blood/organ/tissue weights for males and females from birth to 250 kg, which can be directly used to help parameterize PBPK models. In contrast to other black/white anthropomorphic measurements, the data demonstrated no observable or statistical difference in weights for any organ/tissue between individuals identified as black or white in the autopsy reports.

A physiologically based pharmacokinetic model was developed for acrylamide (AA) and three of its metabolites: glycidamide (GA) and the glutathione conjugates of acrylamide (AA-GS) and glycidamide (GA-GS). Liver GA-DNA adducts and hemoglobin (Hb) adducts with AA and GA were included as pharmacodynamic components of the model. Serum AA and GA concentrations combined with urinary elimination levels for all four components from male and female mice and rats were simulated from iv and oral administration of 0.1 mg/kg AA or 0.12 mg/kg GA. Adduct formation and decay rates were determined from a 6 week exposure to approximately 1 mg/kg AA in the drinking water and subsequent 6 week nonexposure period. Human urinary excretion data and Hb adduct data were utilized to extrapolate to a human model. The steady-state human liver GA-DNA adduct level from exposure to background levels of AA in the diet was predicted to be between 0.06 and 0.26 adducts per 10(8) nucleotides.