Motherhood after cancer: fertility and utilisation of fertility-preservation methods.

PURPOSE: Due to modern and individualised treatments, women at reproductive age have a high survival rate after cancer therapy. What are pregnancy and birth rates of women after cancer and how often do they use cryopreserved ovarian tissue or gametes? METHODS: From 2007 to 2015, 162 women aged 26.7 ± 6.9 years were counselled for fertility preservation at a single University Fertility Centre. A questionnaire study was performed in average 3 and 6 years after the diagnosis of cancer. The women were asked about their fertility, partnership, family planning, and pregnancy history. 72 women (51%) answered a written questionnaire in 2016. 59 women were reached again by phone in 2019 (82%). RESULTS: The preferred method of fertility preservation was ovarian tissue cryopreservation (n = 36, 50%); none of the women had ovarian hyperstimulation in order to cryopreserve oocytes. About 3 years after treatment, 37 women of 72 women (51%) of the women with a mean age of 29.9 years had a strong wish to conceive. 21/72 (29%) had actively tried to conceive after successful cancer treatment; eight women (11%) were already pregnant or had children. Six years after cancer diagnosis 16/59 (27%) women had ongoing anticancer treatment. 12/59 (20%) were pregnant or had children, while 39% (23/59) had no menstrual cycle. Only one woman used her cryopreserved ovarian tissue, but did not become pregnant. CONCLUSION: After cancer and gonadotoxic treatment, women's desire to have a child is substantial. In this study, the rate of spontaneous pregnancies and births was 20% 6 years after gonadotoxic therapies. Not every woman, however, has the opportunity to conceive: factors impairing fertility include ongoing cancer treatment or persistent disease, no partner, no menstrual cycle, as well as other reasons for infertility.

Use of a probabilistic PBPK/PD model to calculate Data Derived Extrapolation Factors for chlorpyrifos.

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model combined with Monte Carlo analysis of inter-individual variation was used to assess the effects of the insecticide, chlorpyrifos and its active metabolite, chlorpyrifos oxon in humans. The PBPK/PD model has previously been validated and used to describe physiological changes in typical individuals as they grow from birth to adulthood. This model was updated to include physiological and metabolic changes that occur with pregnancy. The model was then used to assess the impact of inter-individual variability in physiology and biochemistry on predictions of internal dose metrics and quantitatively assess the impact of major sources of parameter uncertainty and biological diversity on the pharmacodynamics of red blood cell acetylcholinesterase inhibition. These metrics were determined in potentially sensitive populations of infants, adult women, pregnant women, and a combined population of adult men and women. The parameters primarily responsible for inter-individual variation in RBC acetylcholinesterase inhibition were related to metabolic clearance of CPF and CPF-oxon. Data Derived Extrapolation Factors that address intra-species physiology and biochemistry to replace uncertainty factors with quantitative differences in metrics were developed in these same populations. The DDEFs were less than 4 for all populations. These data and modeling approach will be useful in ongoing and future human health risk assessments for CPF and could be used for other chemicals with potential human exposure.

Chlorpyrifos PBPK/PD model for multiple routes of exposure.

1. Chlorpyrifos (CPF) is an important pesticide used to control crop insects. Human Exposures to CPF will occur primarily through oral exposure to residues on foods. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been developed that describes the relationship between oral, dermal and inhalation doses of CPF and key events in the pathway for cholinergic effects. The model was built on a prior oral model that addressed age-related changes in metabolism and physiology. This multi-route model was developed in rats and humans to validate all scenarios in a parallelogram design. 2. Critical biological effects from CPF exposure require metabolic activation to CPF oxon, and small amounts of metabolism in tissues will potentially have a great effect on pharmacokinetics and pharmacodynamic outcomes. Metabolism (bioactivation and detoxification) was therefore added in diaphragm, brain, lung and skin compartments. Pharmacokinetic data are available for controlled human exposures via the oral and dermal routes and from oral and inhalation studies in rats. The validated model was then used to determine relative dermal versus inhalation uptake from human volunteers exposed to CPF in an indoor scenario.

A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: development and validation.

Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages.

In vitro age-dependent enzymatic metabolism of chlorpyrifos and chlorpyrifos-oxon in human hepatic microsomes and chlorpyrifos-oxon in plasma.

Age-dependent chlorpyrifos (CPF) metabolism was quantified by in vitro product formation in human hepatic microsomes (ages 13 days to 75 years) and plasma (ages 3 days to 43 years) with gas chromatography-mass spectrometry. Hepatic CPF cytochrome P450 desulfuration [CPF to chlorpyrifos-oxon (CPF-oxon)] and dearylation (CPF to 3,5,6-trichloro-2-pyridinol) V(max) values were 0.35 ± 0.21 and 0.73 ± 0.38 nmol · min(-1) · mg microsomal protein (-1) (mean ± S.D.), respectively. The mean (±S.D.) hepatic CPF-oxon hydrolysis (chlorpyrifos-oxonase [CPFOase]) V(max) was 78 ± 44 nmol · min(-1) · mg microsomal protein (-1). None of these hepatic measures demonstrated age-dependent relationships on a per microsomal protein basis using linear regression models. Ratios of CPF bioactivation to detoxification (CPF desulfuration to dearylation) V(max) values were consistent across ages. CPFOase in plasma demonstrated age-dependent increases on a volume of plasma basis, as did total plasma protein levels. Mean (±S.D.) CPF-oxon hydrolysis V(max) values for children <6 months of age and adults (≥16 years) were 1900 ± 660 and 6800 ± 1600 nmol · min(-1) · ml(-1), respectively, and at environmental exposure levels, this high- capacity enzyme is likely to be sufficient even in infants. Plasma samples were phenotyped for paraoxonase status, and frequencies were 0.5, 0.4, and 0.1 for QQ, QR, and RR phenotypes, respectively. These results will be integrated into a physiologically based pharmacokinetic and pharmacodynamic model for CPF and, once integrated, will be useful for assessing biological response to CPF exposures across life stages.

Development of a source-to-outcome model for dietary exposures to insecticide residues: an example using chlorpyrifos.

Probabilistic models of interindividual variation in exposure and response were linked to create a source-to-outcome population model. This model was used to investigate cholinesterase inhibition from dietary exposures to an insecticide (chlorpyrifos) in populations of adults and 3 year old children. A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was used to calculate the variation in sensitivity occurring from interindividual variability in physiology, metabolism, and physical activity levels. A dietary intake model characterizes the variation in dietary insecticide exposures and variation in anthropometry in the populations. Published equations were used to describe the necessary physiology for each simulated individual based on the anthropometry from the dietary intake model. The model of the interindividual variation in response to chlorpyrifos was developed by performing a sensitivity analysis on the PBPK/PD model to determine the parameters that drive variation in pharmacodynamics outcomes (brain and red blood cell acetylcholinesterase inhibition). Distributions of interindividual variation were developed for parameters with the largest impact; the probabilistic model sampled from these distributions. The impact of age and interindividual variation on sensitivity at the doses that occur from dietary exposures, typically orders of magnitude lower than exposures assessed in toxicological studies, was assessed using the source-to-outcome model. The resulting simulations demonstrated that metabolic detoxification capacity was sufficient to prevent significant brain and red blood cell acetylcholinesterase inhibition, even in individuals with the lowest detoxification potential. Age-specific pharmacokinetic and pharmacodynamic parameters did not predict differences in susceptibility between adults and children. In the future, the approach of this case study could be used to assess the risks from low level exposures to other chemicals.

Application of a source-to-outcome model for the assessment of health impacts from dietary exposures to insecticide residues.

The paper presents a case study of the application of a "source-to-outcome" model for the evaluation of the health outcomes from dietary exposures to an insecticide, chlorpyrifos, in populations of adults (age 30) and children (age 3). The model is based on publically-available software programs that characterize the longitudinal dietary exposure and anthropometry of exposed individuals. These predictions are applied to a validated PBPK/PD model to estimate interindividual and longitudinal variation in brain and RBC AChE inhibition (key events) and chlorpyrifos concentrations in blood and TCPy in urine (biomarkers of exposure). The predicted levels of chlorpyrifos and TCPy are compared to published measurements of the biomarkers. Predictions of RBC AChE are compared to levels of inhibition associated with reported exposure-related effects in humans to determine the potential for the occurrence of adverse cholinergic effects. The predicted distributions of chlorpyrifos in blood and TCPy in urine were found to be reasonably consistent with published values, supporting the predictive value of the exposure and PBPK portions of the source-to-outcome model. Key sources of uncertainty in predictions of dietary exposures were investigated and found to have a modest impact on the model predictions. Future versions of this source-to-outcome model can be developed that consider advances in our understanding of metabolism, to extend the approach to other age groups (infants), and address intakes from other routes of exposure.

In vitro measurements of metabolism for application in pharmacokinetic modeling.

Human risk and exposure assessments require dosimetry information. Species-specific tissue dose response will be driven by physiological and biochemical processes. While metabolism and pharmacokinetic data are often not available in humans, they are much more available in laboratory animals; metabolic rate constants can be readily derived in vitro. The physiological differences between laboratory animals and humans are known. Biochemical processes, especially metabolism, can be measured in vitro and extrapolated to account for in vivo metabolism through clearance models or when linked to a physiologically based pharmacological (PBPK) model to describe the physiological processes, such as drug delivery to the metabolic organ. This review focuses on the different organ, cellular, and subcellular systems that can be used to measure in vitro metabolic rate constants and how those data are extrapolated to be used in biologically based modeling. NOTICE: The views expressed in this paper are those of the authors and do not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

In vitro glutathione conjugation of methyl iodide in rat, rabbit, and human blood and tissues.

Methyl iodide (MeI) is an intermediate in the manufacture of some pesticides and pharmaceuticals, and is under review for US registration as a non-ozone depleting alternative for methyl bromide for pre-plant soil fumigation. MeI is primarily metabolized via conjugation with glutathione (GSH), with further metabolism to S-methyl cysteine and methanethiol. To facilitate extrapolations of animal pharmacokinetic data to humans, rate constants for the GSH metabolism of MeI were determined in cytosols prepared from the liver and kidneys of rats, human donors, female rabbits, and rabbit fetuses, from rabbit olfactory and respiratory epithelium, and from rabbit and rat blood using a headspace vial equilibration technique and two-compartment mathematical model. MeI was metabolized in liver and kidney from adults of all three species, but metabolism was not detectable in fetal rabbit kidney. Maximal metabolic rates (V(max)) were similar in liver from rat and human donors (approximately 40 and 47 nmol/min/mg, respectively) whereas the V(max) rates in kidney cytosols varied approximately three-fold between the three species. No difference was observed in the loss of MeI from active and inactive whole blood from either rats or rabbits. The metabolism in olfactory and respiratory epithelial cytosol had Michaelis-Menten constant (K(m)) values that were several times higher than for any other tissue, suggesting essentially first-order metabolism in the nose. The metabolism of MeI in human liver cytosol prepared from five individual donors indicated two potential populations, one high affinity/low capacity and one with a lower affinity but higher capacity.

Physiologically based pharmacokinetic modeling of 1,4-Dioxane in rats, mice, and humans.

1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

An age-dependent physiologically based pharmacokinetic/pharmacodynamic model for the organophosphorus insecticide chlorpyrifos in the preweanling rat.

Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance are CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (B-est) and PON-1 (A-esterase) detoxification of CPF-oxon to TCP. In the current study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue B-est levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue cholinesterase (ChE) levels. In addition, age-dependent changes in brain, liver, and fat volumes and brain blood flow were obtained from the literature and used in the simulations. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent nonlinear increase in CPF-oxon concentration may potentially result from both the depletion of nontarget B-est and a lower PON-1 metabolic capacity in younger animals. The PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics, and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.

Age-related brain cholinesterase inhibition kinetics following in vitro incubation with chlorpyrifos-oxon and diazinon-oxon.

Chlorpyrifos and diazinon are two commonly used organophosphorus insecticides (OPs), and their primary mechanism of action involves the inhibition of acetylcholinesterase by their metabolites chlorpyrifos-oxon (CPO) and diazinon-oxon (DZO), respectively. The study objectives were to assess the in vitro age-related inhibition kinetics of neonatal rat brain cholinesterase (ChE) for CPO and DZO by estimating the bimolecular inhibitory rate constant (k(i)) values. Brain ChE inhibition and k(i) values following CPO and DZO incubation with neonatal Sprague-Dawley rat brain homogenates were determined at postnatal day (PND) 5, 12, and 17 and compared with the corresponding inhibition and k(i) values obtained in the adult rat. A modified Ellman method was utilized for measuring the ChE activity. CPO caused a greater ChE inhibition than DZO as evidenced from the estimated k(i) values of both compounds. Neonatal brain ChE inhibition kinetics exhibited a marked age-related sensitivity to CPO, with the order of ChE inhibition being PND 5 > PND 7 > PND 17 with k(i) values of 0.95, 0.50, and 0.22 nM(-1)hr(-1), respectively. In contrast, DZO ChE inhibition was not age related in the neonatal brain, and the estimated k(i) value at all PND ages was 0.02 nM(-1)hr(-1). These results demonstrated an age- and OP-selective inhibition of rat brain ChE, which may be critically important in understanding the potential sensitivity of juveniles to specific OPs exposures.

Metabolic rate constants for hydroquinone in F344 rat and human liver isolated hepatocytes: application to a PBPK model.

Hydroquinone (HQ) is an important industrial chemical that also occurs naturally in foods and in the leaves and bark of a number of plant species. Exposure of laboratory animals to HQ may result in species-, sex-, and strain-specific nephrotoxicity. The sensitivity of male F344 versus female F344 and Sprague-Dawley rats or B6C3F1 mice appears to be related to differences in the rates of formation of key nephrotoxic metabolites. Metabolic rate constants for the conversion of HQ through several metabolic steps to the mono-glutathione conjugate and subsequent detoxification via mercapturic acid formation were measured in suspension cultures of hepatocytes isolated from male F-344 rats and humans. A mathematic kinetic model was used to analyze each metabolic step by simultaneously fitting the disappearance of each substrate and the appearance of subsequent metabolites. An iterative, nested approach was used whereby downstream metabolites were considered first, and the model was constrained by the requirement that rate constants determined during analysis of individual steps must also satisfy the complete, integrated metabolism scheme, including competitive pathways. The results from this study indicated that the overall capacity for metabolism of HQ and its mono-glutathione conjugate is greater in hepatocytes from humans than in those from rats, suggesting a greater capacity for detoxification of the glutathione conjugates in humans. Metabolic rate constants were applied to an existing physiologically based pharmacokinetic model, which was used to predict total glutathione metabolites produced in the liver. The results showed that body burdens of these metabolites will be much higher in rats than in humans.

Mode of action and pharmacokinetic studies of 2-butoxyethanol in the mouse with an emphasis on forestomach dosimetry.

Chronic inhalation studies with 2-butoxyethanol (BE) conducted by the National Toxicology Program identified the forestomach and liver of B6C3F1 mice as target organs for tumorigenicity (NTP, 2000). Previous studies have shown that the liver tumors likely resulted from chronic hemolysis-induced oxidative stress. For the forestomach lesions seen in mice, chronic contact irritation (cytotoxicity) and regenerative hyperplasia are hypothesized to result in forestomach tumor development. To test this hypothesis, several experiments were conducted to address the sensitivity of the mouse forestomach to BE administered by various routes. Oral administration of undiluted BE was shown to cause irritation and a compensatory proliferative response in the mouse forestomach, confirming that direct contact between the forestomach and BE, which can occur via grooming of BE condensed on the fur during inhalation exposures, can cause irritation. However, only small amounts of BE (<10 mg/kg) were detected on the fur of mice at the end of 6-h, whole-body or nose-only inhalation exposures to the highest concentration used in the NTP chronic inhalation studies (250 ppm). Furthermore, no significant differences were detected in the end-exposure blood concentrations of BE and butoxyacetic acid (BAA) between these types of exposures. In addition, parenteral administration of BE (ip and sc injection) also resulted in forestomach lesions, indicating that there may be sources other than grooming for BE- or BAA-induced forestomach irritation. In the pharmacokinetic study, BE and, to a lesser extent, BAA was eliminated more slowly from the forestomach tissue of mice than from blood or other tissues, following either oral gavage or ip injection. The forestomach was the only tissue with detectable levels of BE at 24 h. BE and BAA were both excreted in the saliva and were present in stomach contents for a prolonged period of time following these routes of exposure, which may further contribute to forestomach tissue dosimetry. Thus, there appear to be multiple mechanisms behind the increased levels of BE and BAA in the forestomach tissue of mice, which together can contribute to a prolonged contact irritation, compensatory hyperplasia, and tumorigenicity in mice. The relevance of these effects in humans, who lack a forestomach, is questionable.

PBPK modeling of the percutaneous absorption of perchloroethylene from a soil matrix in rats and humans.

Perchloroethylene (PCE) is a widely used volatile organic chemical. Exposures to PCE are primarily through inhalation and dermal contact. The dermal absorption of PCE from a soil matrix was compared in rats and humans using real-time MS/MS exhaled breath technology and physiologically based pharmacokinetic (PBPK) modeling. Studies with rats were performed to compare the effects of loading volume, concentration, and occlusion. In rats, the percutaneous permeability coefficient (K(P)) for PCE was 0.102 +/- 0.017, and was independent of loading volume, concentration, or occlusion. Exhaled breath concentrations peaked within 1 h in nonoccluded exposures, but were maintained over the 5 h exposure period when the system was occluded. Three human volunteers submerged a hand in a container of PCE-laden soil for 2 h and their exhaled breath was continually monitored during and for 2.5 h following exposure. The absorption and elimination kinetics of PCE were slower in these subjects than initially predicted based upon the PBPK model developed from rat dermal kinetic data. The resulting K(P) for humans was over 100-fold lower than for the rat utilizing a single, well-stirred dermal compartment. Therefore, two additional PBPK skin compartment models were evaluated: a parallel model to simulate follicular uptake and a layered model to portray a stratum corneum barrier. The parallel dual dermal compartment model was not capable of describing the exhaled breath kinetics, whereas the layered model substantially improved the fit of the model to the complex kinetics of dermal absorption through the hand. In real-world situations, percutaneous absorption of PCE is likely to be minimal.

Skin absorption and human risk assessment.

A common practice is to assume that percutaneous absorption does not significantly contribute to total bioavailability and therefore, absorption through other routes is more important to human risk assessment. The skin can represent a significant barrier to absorption, but some substances are absorbed to a significant extent. Since there is a potential for percutaneous penetration that is not consistent between species or substances, the assessment of the potential contribution of total body burden from dermal exposures should be considered. This review briefly discusses some theories, practices, and factors that affect percutaneous absorption with an emphasis on how percutaneous absorption evaluations apply to human risk assessment.

Noninvasive biomonitoring approaches to determine dosimetry and risk following acute chemical exposure: analysis of lead or organophosphate insecticide in saliva.

There is a need to develop approaches for assessing risk associated with acute exposures to a broad range of metals and chemical agents and to rapidly determine the potential implications to human health. Noninvasive biomonitoring approaches are being developed using reliable portable analytical systems to quantitate dosimetry utilizing readily obtainable body fluids, such as saliva. Saliva has been used to evaluate a broad range of biomarkers, drugs, and environmental contaminants, including heavy metals and pesticides. To advance the application of noninvasive biomonitoring a microfluidic/electrochemical device has also been developed for the analysis of lead (Pb), using square-wave anodic stripping voltametry. The system demonstrates a linear response over a broad concentration range (1-2000 ppb) and is capable of quantitating saliva Pb in rats orally administered acute doses of Pb acetate. Appropriate pharmacokinetic analyses have been used to quantitate systemic dosimetry based on determination of saliva Pb concentrations. In addition, saliva has recently been used to quantitate dosimetry following exposure to the organophosphate insecticide chlorpyrifos in a rodent model system by measuring the major metabolite, trichloropyridinol, and saliva cholinesterase inhibition following acute exposures. These results suggest that technology developed for noninvasive biomonitoring can provide a sensitive and portable analytical tool capable of assessing exposure and risk in real-time. By coupling these noninvasive technologies with pharmacokinetic modeling it is feasible to rapidly quantitate acute exposure to a broad range of chemical agents. In summary, it is envisioned that once fully developed, these monitoring and modeling approaches will be useful for evaluating acute exposure and health risk.

Hydroquinone PBPK model refinement and application to dermal exposure.

A physiologically based pharmacokinetic (PBPK) model for hydroquinone (HQ) was refined to include an expanded description of HQ-glucuronide metabolites and a description of dermal exposures to support route-to-route and cross-species extrapolation. Total urinary excretion of metabolites from in vivo rat dermal exposures was used to estimate a percutaneous permeability coefficient (K(p); 3.6×10(-5) cm/h). The human in vivo K(p) was estimated to be 1.62×10(-4) cm/h, based on in vitro skin permeability data in rats and humans and rat in vivo values. The projected total multi-substituted glutathione (which was used as an internal dose surrogate for the toxic glutathione metabolites) was modeled following an exposure scenario based on submersion of both hands in a 5% aqueous solution of HQ (similar to black and white photographic developing solution) for 2 h, a worst-case exposure scenario. Total multi-substituted glutathione following this human dermal exposure scenario was several orders of magnitude lower than the internal total glutathione conjugates in rats following an oral exposure to the rat NOEL of 20 mg/kg. Thus, under more realistic human dermal exposure conditions, it is unlikely that toxic glutathione conjugates (primarily the di- and, to a lesser degree, the tri-glutathione conjugate) will reach significant levels in target tissues.

Comparative pharmacokinetics of chlorpyrifos versus its major metabolites following oral administration in the rat.

Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of both in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual's contact with both the parent pesticide and exposure to these metabolites in the environment. In the current study, simultaneous dosing of 13C- or 2H-isotopically labeled CPF (13C-labeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare the pharmacokinetics and metabolism of CPF with TCPy, and DETP. The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 micromol/kg; approximately 5 mg/kg CPF). Major differences in the pharmacokinetics between CPF and metabolite doses were observed within the first 3h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (> or =3h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or (2)H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact their pharmacokinetics.

Quantitative risk analysis for N-methyl pyrrolidone using physiologically based pharmacokinetic and benchmark dose modeling.

Establishing an occupational exposure limit (OEL) for N-methyl pyrrolidone (NMP) is important due to its widespread use as a solvent. Based on studies in rodents, the most sensitive toxic end point is a decrease in fetal/pup body weights observed after oral, dermal, and inhalation exposures of dams to NMP. Evidence indicates that the parent compound is the causative agent. To reduce the uncertainty in rat to human extrapolations, physiologically based pharmacokinetic (PBPK) models were developed to describe the pharmacokinetics of NMP in both species. Since in utero exposures are of concern, the models considered major physiological changes occurring in the dam or mother over the course of gestation. The rat PBPK model was used to determine the relationship between NMP concentrations in maternal blood and decrements in fetal/pup body weights following exposures to NMP vapor. Body weight decrements seen after vapor exposures occurred at lower NMP blood levels than those observed after oral and dermal exposures. Benchmark dose modeling was used to better define a point of departure (POD) for fetal/pup body weight changes based on dose-response information from two inhalation studies in rats. The POD and human PBPK model were then used to estimate the human equivalent concentrations (HECs) that could be used to derive an OEL value for NMP. The geometric mean of the PODs derived from the rat studies was estimated to be 350 mg h/l (expressed in terms of internal dose), a value which corresponds to an HEC of 480 ppm (occupational exposure of 8 h/day, 5 days/week). The HEC is much higher than recently developed internationally recognized OELs for NMP of 10-20 ppm, suggesting that these OELs adequately protect workers exposed to NMP vapor.