Search

A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Pharmacokinetic data for parent and metabolite were collected from several tissues after intravenous administration of triadimefon to male Sprague-Dawley rats. The model adequately simulated peak blood and tissue concentrations but predicted more rapid clearance of both triadimefon and triadimenol from blood and tissues. Reverse metabolism of triadimenol to triadimefon in the liver was explored as a possible explanation of this slow clearance, with significant improvement in model prediction. The amended model was extrapolated to humans using in vitro metabolic constants measured in human hepatic microsomes. Human equivalent doses (HEDs) were calculated for a rat no observable adverse effect level (NOAEL) dose of 3.4mg/kg/day using area under the concentration curve (AUC) in brain and blood for triadimefon and triadimenol as dosimetrics. All dosimetric-based HEDs were 25-30 fold above the human oral reference dose of 0.03mg triadimefon/kg/day, but did not account for intra-human variability or pharmacodynamic differences. Ultimately, derivations of this model will be able to better predict the exposure profile of these and other conazole fungicides in humans.

Understanding the potential differences in metabolic capacity and kinetics between various common laboratory species as well as between genders is an important facet of chemical risk assessment that is often overlooked, particularly for chemicals which undergo non-cytochrome P450 mediated metabolism. The use of physiologically based pharmacokinetic (PBPK) models to better describe chemical exposure is made more powerful by incorporation of high quality in vitro kinetic data. To this end, metabolism of the conazole fungicide triadimefon was studied in hepatic microsomes of both genders of SD rats and CD-1 mice. Triadimefon depletion and triadimenol formation were measured in each type of microsomes. Michaelis-Menten regressions were applied to metabolic data and V(MAX) and the Michaelis constant (K(M)) values calculated. Male SD rats metabolized triadimefon more rapidly than female SD rats or either gender of CD-1 mouse. K(M) values were in the micromolar range, indicating the possibility of competitive inhibition with endogenous substrates. Intrinsic clearances derived from kinetic parameters indicate that triadimefon metabolism is blood-flow limited in all organisms studied with the possible exception of female rat. The in vitro half-life method was investigated as a less resource intensive method for the derivation of intrinsic clearance, and was found to be useful as a complement to the traditional Michaelis-Menten approach.

Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for use in food can liners. Worldwide biomonitoring studies consistently find high prevalence of BPA conjugates in urine consistent with pervasive exposure at levels typically below 1 μg/kg bw/day. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult female CD-1 mice following intravenous (IV) injection, which produces higher serum levels by circumventing the processes of absorption from the GI tract and presystemic metabolism that occur after oral administration. Deuterated BPA (100 μg/kg bw) was used to avoid interference by background contamination from trace amounts of native BPA. Additionally, the pharmacokinetics of unconjugated BPA were determined in adipose tissue, a proposed site of action and "depot" for BPA. After IV injection, unconjugated BPA rapidly distributed out of the circulation (t(1/2)=0.2 h) and terminal elimination also proceeded rapidly (t(1/2)=0.8 h). Consistent with the degree of aqueous solubility, lipid/water solubility ratio, and partitioning from blood into adipose tissue in vivo, the levels of unconjugated BPA in mouse adipose tissue rapidly reached a maximal level (0.25 h) that did not exceed the serum maximum at the initial sampling time (0.08 h). Terminal elimination of unconjugated BPA from adipose tissue (t(1/2)=7.0 h) was similar to that for conjugated BPA in serum (t(1/2)=6.6 h) and

Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of >90% of Americans aged 6-60 suggests ubiquitous and frequent exposure at levels largely below 1 μg/kg bw/d. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult and neonatal CD-1 mice by oral and subcutaneous (SC) injection routes. Deuterated BPA was used to avoid issues of background contamination. Significant inverse relationships were observed between postnatal age and measures of internal exposures (C(max)) to unconjugated BPA after oral administration. Phase II conjugation, area under the time-concentration curve (AUC), and elimination half-time of unconjugated BPA were also inversely related to age. In postnatal day (PND) 3 mice, the combination of under-developed Phase II metabolism, rapid absorption, and slow elimination kinetics led to equivalent internal exposures for unconjugated BPA from oral and SC routes; however, maturing metabolic capabilities in PND 10 and older mice, led to large and significant route effects. The significant inverse age-related developmental profiles from PND 3 through adulthood for unconjugated BPA internal exposure metrics from oral administration to CD-1 mice and Sprague-Dawley rats were remarkably similar; however, the developmental profile was quite different for neonatal rhesus monkeys in which small insignificant age-related differences were observed. These results suggest that an adverse effect from BPA observed in rodent models, attributable to exposure during a discrete time period of neonatal development, would be less likely for comparable neonatal primate dosing based on internal dosimetry. On the other hand in all adults of all species studied, including humans, a low oral dose of BPA produced similarly small internal exposures for the unconjugated form, reflecting the dominant effect of presystemic Phase II metabolism.

Cadmium (Cd) occurs naturally in the environment and the general population's exposure to it is predominantly through diet. Chronic Cd exposure is a public health concern because Cd is a known carcinogen; it accumulates in the body and causes kidney damage. The National Health and Nutritional Examination Survey (NHANES) has measured urinary Cd; the 2003-2004 NHANES survey cycle reported estimates for 2257 persons aged 6 years and older in the Fourth National Report on Human Exposure to Environmental Chemicals. As part of translational research to make computerized models accessible to health risk assessors we re-coded a cadmium model in Berkeley Madonna simulation language. This model was used in our computational toxicology laboratory to predict the urinary excretion of cadmium. The model simulated the NHANES-measured data very well from ages 6 to 60+ years. An unusual increase in Cd urinary excretion was observed among 6-11-year-olds, followed by a continuous monotonic rise into the seventh decade of life. This observation was also made in earlier studies that could be life stage-related and a function of anatomical and phsysiological changes occurring during this period of life. Urinary excretion of Cd was approximately twofold higher among females than males in all age groups. The model describes Cd's cumulative nature in humans and accommodates the observed variation in exposure/uptake over the course of a lifetime. Such models may be useful for interpreting biomonitoring data and risk assessment.