Rhyne Setzer - Academia.edu (original) (raw)

Papers by Rhyne Setzer

Toxicological Sciences, 2006

The U.S. Environmental Protection Agency (EPA) is developing methods for utilizing computational ... more The U.S. Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS), and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. This chemical prioritization research program, entitled ''ToxCast,'' is being initiated with the purpose of developing the ability to forecast toxicity based on bioactivity profiling. The proof-of-concept phase of ToxCast will focus upon chemicals with an existing, rich toxicological database in order to provide an interpretive context for the ToxCast data. This set of several hundred reference chemicals will represent numerous structural classes and phenotypic outcomes, including tumorigens, developmental and reproductive toxicants, neurotoxicants, and immunotoxicants. The ToxCast program will evaluate chemical properties and bioactivity profiles across a broad spectrum of data domains: physical-chemical, predicted biological activities based on existing structure-activity models, biochemical properties based on HTS assays, cell-based phenotypic assays, and genomic and metabolomic analyses of cells. These data will be generated through a series of external contracts, along with collaborations across EPA, with the National Toxicology Program, and with the National Institutes of Health Chemical Genomics Center. The resulting multidimensional data set provides an informatics challenge requiring appropriate computational methods for integrating various chemical, biological, and toxicological data into profiles and models predicting toxicity.

Food and Chemical Toxicology, 2010

Sudan I is generally considered mutagenic based on various in vitro and in vivo tests and is carc... more Sudan I is generally considered mutagenic based on various in vitro and in vivo tests and is carcinogenic in the rat. Dose-response modelling of the data for hepatocellular adenomas in male rats gave a BMDL 10 of 7.3 mg/kg-bw/day. Sudan I is an unauthorised substance that might be present in food intermittently. The great variability and uncertainties in the human exposure data which are country specific, depending on consumption patterns and methodology used, resulted in a large range of MOE values (from 30 to 2,000,000).

BMC Bioinformatics, 2008

Background: Bioactivity profiling using high-throughput in vitro assays can reduce the cost and t... more Background: Bioactivity profiling using high-throughput in vitro assays can reduce the cost and time required for toxicological screening of environmental chemicals and can also reduce the need for animal testing. Several public efforts are aimed at discovering patterns or classifiers in highdimensional bioactivity space that predict tissue, organ or whole animal toxicological endpoints. Supervised machine learning is a powerful approach to discover combinatorial relationships in complex in vitro/in vivo datasets. We present a novel model to simulate complex chemicaltoxicology data sets and use this model to evaluate the relative performance of different machine learning (ML) methods. Results: The classification performance of Artificial Neural Networks (ANN), K-Nearest Neighbors (KNN), Linear Discriminant Analysis (LDA), Naïve Bayes (NB), Recursive Partitioning and Regression Trees (RPART), and Support Vector Machines (SVM) in the presence and absence of filter-based feature selection was analyzed using K-way cross-validation testing and independent validation on simulated in vitro assay data sets with varying levels of model complexity, number of irrelevant features and measurement noise. While the prediction accuracy of all ML methods decreased as non-causal (irrelevant) features were added, some ML methods performed better than others. In the limit of using a large number of features, ANN and SVM were always in the top performing set of methods while RPART and KNN (k = 5) were always in the poorest performing set. The addition of measurement noise and irrelevant features decreased the classification accuracy of all ML methods, with LDA suffering the greatest performance degradation. LDA performance is especially sensitive to the use of feature selection. Filter-based feature selection generally improved performance, most strikingly for LDA. Conclusion: We have developed a novel simulation model to evaluate machine learning methods for the analysis of data sets in which in vitro bioassay data is being used to predict in vivo chemical toxicology. From our analysis, we can recommend that several ML methods, most notably SVM and ANN, are good candidates for use in real world applications in this area.

Teratology, 1990

The hypothesis that chemically induced overt maternal toxicity induces a characteristic syndrome ... more The hypothesis that chemically induced overt maternal toxicity induces a characteristic syndrome of adverse developmental effects in the rat was investigated. Pregnant animals (Sprague-Dawley strain) were dosed by oral gavage with one of a series of compounds on days 6-15 of gestation. These chemicals were diquat (DIQ), ethylene-bis-isothiocyanate (EBIS), toxaphene (TOX), styrene (STY), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenol (2,4,5-Tr), triphenyl tin hydroxide (TPTH), and cacodylic acid (CAC). The compounds were chosen because they exhibited little or no developmental toxicity in previous studies. Dosage levels producing maternal weight loss and/ or lethality were determined from preliminary toxicity studies. Significant maternal weight reductions were noted during the course of treatment with all compounds except CAC and 2,4,5-Tr. Maternal lethality was produced by EBIS, TOX, 2,4,-D, and 2,4,5-Tr. The main treatment-related developmental toxicity noted in litters at term consisted of increased lethality (EBIS, TPTH) and decreased fetal weight (EBIS and CAC). Treatment-related anomalies were seen in litters treated with 2,4-D and TOX (supernumerary ribs) and with EBIS and STY (enlarged renal pelvis). No significant developmental effects were produced with DIQ, or 2,4,5-Tr. This study indicates that overt maternal toxicity as defined by weight loss or mortality is not always associated with the same defined syndrome of adverse developmental effects in the rat.

Journal of Statistical Software, 2010

In this paper we present the R package deSolve to solve initial value problems (IVP) written as o... more In this paper we present the R package deSolve to solve initial value problems (IVP) written as ordinary differential equations (ODE), differential algebraic equations (DAE) of index 0 or 1 and partial differential equations (PDE), the latter solved using the method of lines approach. The differential equations can be represented in R code or as compiled code. In the latter case, R is used as a tool to trigger the integration and post-process the results, which facilitates model development and application, whilst the compiled code significantly increases simulation speed. The methods implemented are efficient, robust, and well documented public-domain Fortran routines. They include four integrators from the ODEPACK package (LSODE, LSODES, LSODA, LSODAR), DVODE and DASPK2.0. In addition, a suite of Runge-Kutta integrators and special-purpose solvers to efficiently integrate 1-, 2-and 3-dimensional partial differential equations are available. The routines solve both stiff and non-stiff systems, and include many options, e.g., to deal in an efficient way with the sparsity of the Jacobian matrix, or finding the root of equations. In this article, our objectives are threefold: (1) to demonstrate the potential of using R for dynamic modeling, (2) to highlight typical uses of the different methods implemented and (3) to compare the performance of models specified in R code and in compiled code for a number of test cases. These comparisons demonstrate that, if the use of loops is avoided, R code can efficiently integrate problems comprising several thousands of state variables. Nevertheless, the same problem may be solved from 2 to more than 50 times faster by using compiled code compared to an implementation using only R code. Still, amongst the benefits of R are a more flexible and interactive implementation, better readability of the code, and access to R's high-level procedures. deSolve is the successor of package odesolve which will be deprecated in the future; it is free software and distributed under the GNU General Public License, as part of the R software project.

Toxicological Sciences, 2007

Physiologically based pharmacokinetic (PBPK) models are used in mode-of-action based risk and saf... more Physiologically based pharmacokinetic (PBPK) models are used in mode-of-action based risk and safety assessments to estimate internal dosimetry in animals and humans. When used in risk assessment, these models can provide a basis for extrapolating between species, doses, and exposure routes or for justifying nondefault values for uncertainty factors. Characterization of uncertainty and variability is increasingly recognized as important for risk assessment; this represents a continuing challenge for both PBPK modelers and users. Current practices show significant progress in specifying deterministic biological models and nondeterministic (often statistical) models, estimating parameters using diverse data sets from multiple sources, using them to make predictions, and characterizing uncertainty and variability of model parameters and predictions. The International Workshop on Uncertainty and Variability in PBPK Models, held 31 Oct-2 Nov 2006, identified the state-of-the-science, needed changes in practice and implementation, and research priorities. For the short term, these include (1) multidisciplinary teams to integrate deterministic and nondeterministic/statistical models; (2) broader use of sensitivity analyses, including for structural and global (rather than local) parameter changes; and (3) enhanced transparency and reproducibility through improved documentation of model structure(s), parameter values, sensitivity and other analyses, and supporting, discrepant, or excluded data. Longer-term needs include (1) theoretical and practical methodological improvements for nondeterministic/statistical modeling; (2) better methods for evaluating alternative model structures; (3) peerreviewed databases of parameters and covariates, and their distributions; (4) expanded coverage of PBPK models across chemicals with different properties; and (5) training and reference materials, such as cases studies, bibliographies/glossaries, model repositories, and enhanced software. The multidisciplinary dialogue initiated by this Workshop will foster the collaboration, research, data collection, and training necessary to make characterizing uncertainty and variability a standard practice in PBPK modeling and risk assessment.

Epidemiological Aspects of Cutaneous Malignant Melanoma, 1994

The benchmark dose (BMD) is the dose of a substance that is expected to result in a prespecified ... more The benchmark dose (BMD) is the dose of a substance that is expected to result in a prespecified level of effect, the benchmark response level or BMR. It is a general approach to characterizing dose response, applicable to any toxicant and endpoint. A BMD is conceptually superior to a "no observed adverse effect level" (NOAEL) for this purpose because of being less determined by experimental design, because it is a precisely defined entity, and because its precision can be estimated. Since a BMD is a single number, just as an NOAEL, it is tempting to use the BMD as a straightforward replacement for the NOAEL in the assessment process for calculating allowable daily intakes. However, the level of toxic response at an NOAEL is unknown, while that at a BMD is well defined. Use of the BMD approach potentially adds consistency and objectivity to the process of deriving reference values (RfDs, RfCs, or ADIs) for setting regulatory levels. To take advantage of this, BMRs need to be selected in a consistent way across studies and endpoints. This paper discusses some issues affecting the selection of BMRs, and presents an example of a BMD calculated for the effects of peripubertal exposure to the fungicide vinclozolin.

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Toxicological Sciences, 2015

We previously integrated dosimetry and exposure with high-throughput screening (HTS) to enhance t... more We previously integrated dosimetry and exposure with high-throughput screening (HTS) to enhance the utility of ToxCast HTS data by translating in vitro bioactivity concentrations to oral equivalent doses (OEDs) required to achieve these levels internally. These OEDs were compared against regulatory exposure estimates, providing an activity-to-exposure ratio (AER) useful for a risk-based ranking strategy. As ToxCast efforts expand (ie, Phase II) beyond food-use pesticides toward a wider chemical domain that lacks exposure and toxicity information, prediction tools become increasingly important. In this study, in vitro hepatic clearance and plasma protein binding were measured to estimate OEDs for a subset of Phase II chemicals. OEDs were compared against high-throughput (HT) exposure predictions generated using probabilistic modeling and Bayesian approaches generated by the U.S. Environmental Protection Agency (EPA) ExpoCast program. This approach incorporated chemical-specific use and national production volume data with biomonitoring data to inform the exposure predictions. This HT exposure modeling approach provided predictions for all Phase II chemicals assessed in this study whereas estimates from regulatory sources were available for only 7% of chemicals. Of the 163 chemicals assessed in this study, 3 or 13 chemicals possessed AERs < 1 or < 100, respectively. Diverse bioactivities across a range of assays and concentrations were also noted across the wider chemical space surveyed. The availability of HT exposure estimation and bioactivity screening tools provides an opportunity to incorporate a risk-based strategy for use in testing prioritization.

Toxicological sciences : an official journal of the Society of Toxicology, 2001

Biologically based dose-response (BBDR) models represent an emerging approach to improving the cu... more Biologically based dose-response (BBDR) models represent an emerging approach to improving the current practice of human health-risk assessment. The concept of BBDR modeling is to incorporate mechanistic information about a chemical that is relevant to the expression of its toxicity into descriptive mathematical terms, thereby providing a quantitative model that will enhance the ability for low-dose and cross-species extrapolation. Construction of a BBDR model for developmental toxicity is particularly complicated by the multitude of possible mechanisms. Thus, a few model assumptions were made. The current study illustrates the processes involved in selecting the relevant information for BBDR modeling, using an established developmental toxicant, 5-fluorouracil (5-FU), as a prototypic example. The primary BBDR model for 5-FU is based on inhibition of thymidylate synthetase (TS) and resultant changes in nucleotide pools, DNA synthesis, cell-cycle progression, and somatic growth. A si...

Mutation research, 1995

Binary combinations of pure chemicals and complex mixtures were evaluated for their ability to pr... more Binary combinations of pure chemicals and complex mixtures were evaluated for their ability to produce additive mutagenicity responses in the spiral and standard Salmonella mutagenicity assays. Single chemicals were selected that were representative of the primary chemical class responsible for much of the mutagenic activity of each complex mixture. The following agents were evaluated in the absence of S9: 1-nitropyrene, diesel exhaust extract, and the chlorinated drinking water mutagen 3-chloro-4-dichloromethyl-5-hydroxy-2-[5H]-furanone (MX). In the presence of S9, the following agents were evaluated: 4-aminobiphenyl, benzo[a]pyrene, and an organic extract from the particulate emissions resulting from the combustion of polyethylene in a rotary kiln incinerator. Binary combinations of the agents within each S9 group were tested. The results were analyzed for additivity by determining whether the difference between the expected response of the binary mixture was significantly differe...

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2001

Vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutagens that, when added to assay plates... more Vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutagens that, when added to assay plates, reduced the spontaneous mutant frequency in Salmonella typhimurium strain TA104 (hisG428, rfa, uvrB, pKM101) by 50%. To date, no study has demonstrated whether or not the antimutagenic effects of an agent are due to a reduction in all classes of mutations or to a reduction in selective classes of mutations. To explore this issue, we have determined the spontaneous mutation spectrum in TA104 as well as the mutation spectrum after treatment of cells with antimutagens at concentrations that produced approximately a 50% reduction in mutant frequency but only a 10% reduction in survival. Statistical analysis revealed no significant difference between the mutation spectra of VAN- and CIN-treated cells. Relative to untreated cells, treatment with either VAN or CIN produced a significant reduction in mutations at GC sites, whereas neither compound produced a significant reduction in mutations at AT sites. Antimutagenesis experiments in hisG428 strains of Salmonella with varying DNA repair backgrounds showed that VAN and CIN require SOS repair genes to produce an antimutagenic effect against spontaneous mutagenesis. Studies evaluating the effect of VAN and CIN on growth rate showed that neither compound suppressed growth relative to untreated cells. To our knowledge, this is the first study to examine if an antimutagen reduced all or just some classes of mutations that were available for reduction.

Background: Rational prioritization of chemicals requires reliable methods for screening on both ... more Background: Rational prioritization of chemicals requires reliable methods for screening on both hazard and exposure potential. High-throughput, typically in vitro, biological activity assays allow the ToxCast™ and Tox21 projects to compare the biological activity of chemicals with known in vivo toxicity to those with little or no in vivo data. Further in vitro assays characterize key aspects of pharmacokinetics and allow in vitro-in vivo extrapolation to predict human uptake (mg/kg/day) that might be sufficient to cause bioactivity in vivoAims: Without similar capability to make quantitative, albeit uncertain, forecasts of exposure, the putative risk due to an arbitrary chemical cannot be rapidly evaluated. Methods: Using physico-chemical properties and provisional chemical use categories, most of the ~10,000 Tox21 chemicals have been evaluated with respect to exposure from near-field sources. A mapping of chemicals to products, and products to uses, has been used to categorize che...

Toxicology and Applied Pharmacology, 2013

Continuous responses (e.g. body weight) are widely used in risk assessment for determining the be... more Continuous responses (e.g. body weight) are widely used in risk assessment for determining the benchmark dose (BMD) which is used to derive a U.S. EPA reference dose. One critical question that is not often addressed in dose-response assessments is whether to model the continuous data as normally or log-normally distributed. Additionally, if lognormality is assumed, and only summarized response data (i.e., mean ± standard deviation) are available as is usual in the peer-reviewed literature, the BMD can only be approximated. In this study, using the "hybrid" method and relative deviation approach, we first evaluate six representative continuous doseresponse datasets reporting individual animal responses to investigate the impact on BMD/BMDL estimates of (1) the distribution assumption and (2) the use of summarized versus individual animal data when a log-normal distribution is assumed. We also conduct simulation studies evaluating model fits to various known distributions to investigate whether the distribution assumption has influence on BMD/BMDL estimates. Our results indicate that BMDs estimated using the hybrid method are more sensitive to the distribution assumption than counterpart BMDs estimated using the relative deviation approach. The choice of distribution assumption has limited impact on the BMD/BMDL estimates when the within dose-group variance is small, while the lognormality assumption is a better choice for relative deviation method when data are more skewed because of its appropriateness in describing the relationship between mean and standard deviation. Additionally, the results suggest that the use of summarized data versus individual response data to characterize log-normal distributions has minimal impact on BMD estimates.

Toxicology and Applied Pharmacology, 1997

Although these results support the hypothesis 29-39. that 5-FU disrupts the MELC cell cycle by de... more Although these results support the hypothesis 29-39. that 5-FU disrupts the MELC cell cycle by depleting dTTP (a perturbation that is reversible by TdR supplementation), they also indi-5-Fluorouracil (5-FU) is a chemotherapeutic agent known to recate that CdR supplementation offers an additional recovery pathtard embryonic growth and induce cleft palate and limb deformities. way. ᭧ 1997 Academic Press The predominant mechanism underlying its toxic action is thought to be inhibition of thymidylate synthetase (TS), and hence thymidine triphosphate (dTTP) synthesis, resulting in alteration of the Embryos exposed to the thymidine analog 5-FU 3 during balance of deoxynucleotide (dNTP) pools and disruption of DNA organogenesis exhibit retarded growth, cleft palate (Abbott synthesis. Indeed, previously we demonstrated retarded cell-cycle progression concurrent with a 60% decrease in TS activity in rat et al., 1993), and limb deformities (Shuey et al., 1994). whole embryos following maternal exposure to 40 mg/kg 5-FU on Because of the extensive literature regarding its metabolism Gestational Day 14 and in the murine erythroleukemic cell (MELC) and mechanisms of action, we previously chose 5-FU as a suspension culture following exposure to 5-25 mM 5-FU for 2 hr. prototype compound for developing a biologically based In the study described herein, we used high-performance liquid dose-response (BBDR) model (Shuey et al., 1994). Such chromatography (HPLC) to demonstrate in both of these model models may serve to improve assessment of the health risks systems that 5-FU exposure results in similar patterns of dNTP associated with exposure by identifying and incorporating perturbations: a prolonged decrease in dTTP and dGTP levels and into a mathematical form the pharmacokinetic and pharmaan increase in dCTP and dATP. In addition, we used centrifugal codynamic sequelae of toxicant exposure (Kavlock and elutriation to synchronize MELC in the phases of the cell cycle (G 0 / Setzer, 1996). Toward that end, we have investigated the G 1 and early S) most sensitive to 5-FU to investigate the ability of contribution of an imbalance in nucleotide pools to the develnucleoside supplementation to mitigate 5-FU-induced toxicity. Our data indicate that following a 2-hr exposure to 5-25 mM 5-FU, opmental toxicity of 5-FU. supplementation with 1-10 mM thymidine (TdR) for 24 hr partially Thus far, three mechanisms have been attributed to the reverses 5-FU-induced toxicity as evidenced by increased cellular toxic action of 5-FU: (1) inhibition of thymidylate synthetase proliferation and cell-cycle progression and amelioration of 5-FU-(TS, which methylates dUMP to form dTMP), resulting in induced perturbations of protein synthesis and cellular membrane dUMP accumulation, dTTP depletion, and decreased DNA permeability compared to unsupplemented 5-FU-exposed cells. synthesis, so-called ''thymineless death'' (Valeriote and However, TdR concentrations §100 mM inhibited growth or were Santinelli, 1984; Kyprianou and Isaacs, 1989); (2) direct cytotoxic. In comparison, supplementation with 10 mM-10 mM of incorporation into mRNA, resulting in inappropriate protein synthesis (Parker and Cheng, 1990); and (3) direct incorpora-1 The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmen-3 Abbreviations used: 5-FU, 5-fluorouracil; GD, gestational day; AdR, 2-tal Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the deoxyadenosine; CdR, 2-deoxycytidine; GdR, 2-deoxyguanosine; NdR, deoxynucleosides; TdR, thymidine; dATP, deoxyadenosine triphosphate; Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. dCTP, deoxycytidine triphosphate; dGTP, deoxyguanosine triphosphate; dTMP, thymidylate; dTTP, thymidine triphosphate; dUMP, deoxyuridylate;

Toxicology, 1995

A biologically-based dose-response (BBDR) model is a mathematical description of the biological e... more A biologically-based dose-response (BBDR) model is a mathematical description of the biological events leading to expression of a toxic response. As an alternative to current approaches in non-cancer risk assessment, such models will reduce uncertainty in that they will provide a more comprehensive description of toxicity. We are involved in construction of a BBDR model for the developmental toxicity of 5-fluorouracil (5-FU) in the rat using multiple approaches. First, to identify critical events in the pathogenesis of 5-FU developmental toxicity, thymidylate synthetase (TS) inhibition and alterations in cell kinetics and growth were examined in embryos following maternal administration of 5-FU on day 14 of gestation. A dose-related decline in TS activity was observed within 1 h; however, maximal inhibition and recovery were similar at 10, 20 and 40 mg/kg. Dose-dependent cell cycle alterations were observed within 4 h after exposure and were maximal at 8 h. Hindlimb growth reduction was observed 24 h after exposure to 40 mg/kg, but not at lower doses. At term hindlimb defects were observed at doses above 30 mg/kg. An integrated dose-response model for hindlimb defects was derived from empirical relationships among these events. The resultant dose-response somewhat over-predicted the developmental toxicity of 5-FU, although results of a Monte Carlo simulation indicated that these data were not incompatible with model predictions. Overall, the results suggest that TS inhibition is a key component of the mechanism of 5-FU developmental toxicology, but the model does not capture all of the critical events in the induction of hindlimb defects. A preliminary mechanistic model for the inhibition of embryonic TS, DNA synthesis and cell cycle following maternal exposure to 5-FU, independently derived from literature data to further examine the potential role of this pathway in its developmental toxicity, predicted a dose-response for TS inhibition and DNA synthesis that closely reflected the observed patterns. These results further suggest that TS inhibition, resultant deficits in DNA synthesis and cell cycle perturbations represent a critical mechanistic pathway in the developmental toxicity of 5-FU.

Toxicology, 2004

One of the most sensitive and reproducible immunotoxic endpoints of 2,3,7,8-tetrachlorodibenzo-p-... more One of the most sensitive and reproducible immunotoxic endpoints of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure is suppression of the antibody response to sheep red blood cells (SRBCs) in mice. Immunosuppression occurs in concert with hepatomegaly and associated induction of several hepatic cytochrome P450 enzymes, including CYP1A2 which is responsible for the hepatic sequestration of TCDD. In this study, TCDD-induced immunosuppression was evaluated in C57BL/6N CYP1A2 (+/+) wild-type and compared with that of age-matched CYP1A2 (−/−) knockout and CYP1A2 (+/−) heterozygous female mice. Groups of mice were given a single gavage dose of 0, 0.03, 0.1, 0.3, 1.0, 3.0 or 10.0 g TCDD/kg, followed 7 days later by immunization with SRBCs. Serum was obtained 5 days after immunization and body, spleen, thymus and liver weights were measured. sheep red blood cell (SRBC) antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA). Anti-SRBC titers were suppressed at 1.0, 1.0 and 0.3 g TCDD/kg for CYP1A2 (+/+), CYP1A2 (+/−), and CYP1A2 (−/−) mice, respectively, which indicated a threefold increase in TCDD-induced immunosuppression for the CYP1A2 (−/−) mice. This increase in TCDD-induced immunosuppression may be due to the inability of CYP1A2 (−/−) mice to sequester TCDD in the liver leading to a higher dose to the immune system. In CYP1A2 (+/+) mice, a dose of 3.0 g TCDD/kg was sufficient to increase the liver weight, while in CYP1A2 (−/−) mice no increase in liver weight was observed. Application of analysis of variance and dose-response modeling approaches indicate that there is little evidence that the immunosuppression dose-response curves, for the three strains, differ in the lower part of the dose-response range. Thus, CYP1A2 is not required for TCDD-induced immunosuppression in the mouse.

Toxicological Sciences, 2012

Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides... more Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides in homes and crops. Managing the risks for pesticides such as permethrin depends on the ability to consider diverse exposure scenarios and their relative risks. Physiologically based pharmacokinetic models of deltamethrin disposition were modified to describe permethrin kinetics in the rat and human. Unlike formulated deltamethrin which consists of a single stereoisomer, permethrin is formulated as a blend of cis-and trans-diastereomers. We assessed time courses for cis-permethrin and trans-permethrin in several tissues (brain, blood, liver, and fat) in the rat following oral administration of 1 and 10 mg/kg permethrin (cis/trans: 40/60). Accurate simulation of permethrin in the rat suggests that a generic model structure is promising for modeling pyrethroids. Human in vitro data and appropriate anatomical information were used to develop a provisional model of permethrin disposition with structures for managing oral, dermal, and inhalation routes of exposure. The human permethrin model was used to evaluate dietary and residential exposures in the U.S. population as estimated by EPA's Stochastic Human Exposure and Dose Simulation model. Simulated cisand trans-DCCA, metabolites of permethrin, were consistent with measured values in the National Health and Nutrition Examination Survey, indicating that the model holds promise for assessing population exposures and quantifying dose metrics.

Toxicological Sciences, 2013

In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-spec... more In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-specific dose regimens into dose metrics such as tissue concentration. These tissue concentrations may then be compared with in vitro bioactivity assays to perhaps identify mechanisms relevant to the lowest observed effect level (LOEL) dose group and the onset of the observed in vivo toxicity. Here, we examine the perfluorinated compounds (PFCs) perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). We analyzed 9 in vivo toxicity studies for PFOA and 13 in vivo toxicity studies for PFOS. Both PFCs caused multiple effects in various test species, strains, and genders. We used a Bayesian pharmacokinetic (PK) modeling framework to incorporate data from 6 PFOA PK studies and 2 PFOS PK studies (conducted in 3 species) to predict dose metrics for the in vivo LOELs and no observed effect levels (NOELs). We estimated PK parameters for 11 combinations of chemical, species, strain, and gender. Despite divergent study designs and species-specific PK, for a given effect, we found that the predicted dose metrics corresponding to the LOELs (and NOELs where available) occur at similar concentrations. In vitro assay results for PFOA and PFOS from EPA's ToxCast project were then examined. We found that most in vitro bioactivity occurs at concentrations lower than the predicted concentrations for the in vivo LOELs and higher than the predicted concentrations for the in vivo NOELs (where available), for a variety of nonimmunological effects. These results indicate that given sufficient PK data, the in vivo LOELs dose regimens, but not necessarily the effects, could have been predicted from in vitro studies for these 2 PFCs.