title: A computer program linking physiologically based pharmacokinetic model with cancer risk assessment for breast-fed infants.
abstract: The risk assessment process predicts the chances of adverse health effects that the toxicant possibly can do to the target organism under expected conditions of exposure. Regulators chose among several mathematical approaches to estimate the risk, but in each case it is necessary to link the dosemetrics of the toxicant with its predicted health effect. In this paper, a computer program is described that allowed us to link a physiologically based pharmacokinetic (PBPK) model for tetrachloroethylene (PCE) in the lactating mother with the estimate of extra cancer risk for breast-fed infants, according to the U.S. Environmental Protection Agency (EPA) methodology. When inhaled by a lactating woman, PCE may partition into breast milk and may be transferred to the breast-fed infant. We have developed and validated experimentally a PBPK model for lactational transfer of PCE in rats, including a quantitative description of a milk compartment and the nursing pup. Subsequently, the model has been scaled to describe human physiology, and was validated with literature data for human cases of PCE exposure. Finally, we linked the dosage predictions of the PBPK model with equations used by EPA to estimate the cancer risk from PCE. The model predictions are in good agreement with both the measured values and those reported in the literature for exposure to PCE. This comparison confirms the usefulness of PBPK modeling in risk assessments.
authors.affiliation: ManTech Environmental Technology, Inc., Dayton, OH 45437, USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Byczkowski
authors.forename: J W
authors.initials: JW
authors.lastname: Fisher
mesh_terms: D000393:Air Pollutants / Q000493:pharmacokinetics; D000818:Animals; D001942:Breast Feeding; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005544:Forecasting; D006801:Humans; D007231:Infant, Newborn; D007774:Lactation; D008895:Milk, Human / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced*; D009374:Neoplasms, Experimental / Q000139:chemically induced; D051381:Rats; D018570:Risk Assessment; D012984:Software; D012986:Software Validation; D013750:Tetrachloroethylene / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D000393:Air Pollutants; D013750:Tetrachloroethylene