A trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in conjunction with physiologically-based pharmacokinetic modeling.
A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10(-6) lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10(-6) risk.
Cronin
W J
WJ
Air Force Institute of Technology, Department of Engineering and Environmental Management, Wright-Patterson Air Force Base, Ohio 45433, USA.
Oswald
E J
EJ
Shelley
M L
ML
Fisher
J W
JW
Flemming
C D
CD
D000280:Administration, Inhalation; D000284:Administration, Oral; D018685:Anesthetics, Inhalation / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D009010:Monte Carlo Method; D009369:Neoplasms / Q000139:chemically induced; D009374:Neoplasms, Experimental / Q000139:chemically induced; D018570:Risk Assessment; D014241:Trichloroethylene / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D014481:United States; D014484:United States Environmental Protection Agency
D018685:Anesthetics, Inhalation; D002273:Carcinogens; D014241:Trichloroethylene