Derivation of no significant risk levels for three lower acrylates: Conclusions and recommendations from an expert panel.

A panel of toxicology, mode of action (MOA), and cancer risk assessment experts was engaged to derive no-significant-risk-levels (NSRLs) for three lower acrylates: methyl acrylate (MA), ethyl acrylate (EA), and 2-ethylhexyl acrylate (2EHA) using the best available science, data, and methods. The review was structured as a five-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included several procedural elements to reduce potential sources of bias and groupthink. Input from the panel for key decisions in the dose-response assessments resulted in NSRL values of 530 µg/day (330-800 µg/day), 640 µg/day (280-670 µg/day), and 1700 µg/day (1300-2700 µg/day) for MA, EA, and 2EHA, respectively. Novel to this approach were the use of nonneoplastic lesions reported at point of contact where tumors have been reported in laboratory rodents, along with nonlinear extrapolation to low doses (uncertainty factor approach) based upon panel recommendations. Confidence in these values is considered medium to high for exposures applied to the routes of exposure tested (inhalation for MA and EA, dermal for 2EHA), but confidence is considered lower when applied to other routes of exposure.

Cancer weight of evidence for three lower acrylates: Conclusions and recommendations from an expert panel.

An international panel of experts was engaged to assess the cancer weight of evidence (WOE) for three lower acrylates: methyl acrylate, ethyl acrylate, and 2-ethylhexyl acrylate. The review was structured as a three-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included procedural elements to reduce bias and groupthink. Based upon the available science, the panel concluded: (1) The MOA for point of contact tumors observed in rodent cancer bioassays that is best supported by available data involves increased cell replication by cytotoxicity and regenerative proliferation; (2) The WOE supports a cancer classification of "Not likely to be carcinogenic to humans" a conclusion that is more in line with an IARC classification of Group 3 rather than Group 2 B; (3) Quantitative cancer potency values based on rodent tumor data are not required for these chemicals; and (4) Human health risk assessment for these chemicals should instead rely on non-cancer, precursor endpoints observed at the point of contact (e.g., hyperplasia). The degree of consensus (consensus scores of 0.84-0.91 out of a maximum score of 1) and degree of confidence (7.7-8.7 out of a maximum score of 10) in the WOE conclusions is considered high.

A perspective on In vitro developmental neurotoxicity test assay results: An expert panel review.

For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial screening, but it is not presently a complete or surrogate approach to determine whether a chemical is a DNT in humans. By itself, the DNT IVB does not have the ability to capture nuances and complexity of the developing nervous system and associated outcomes including behavioral ontogeny, motor activity, sensory function, and learning/memory. Presently, such developmental landmarks cannot be adequately assessed in the DNT IVB or by other NAMs. The expert panel (all who serve as co-authors of this review) recommended that additional data generation and validation is required before the DNT IVB can be considered for application within global regulatory frameworks for decision-making.

An evaluation of reproductive toxicity studies and data interpretation of N-methylpyrrolidone for risk assessment: An expert panel review.

An expert panel was assembled to evaluate reproductive toxicology study data and their application to health risk assessment to provide input on the data quality, interpretation, and application of data from three multi-generation reproductive toxicity studies of N-methylpyrrolidone (NMP). Panelists were engaged using a double-blinded, modified Delphi format that consisted of three rounds. Key studies were scored using the U.S. Environmental Protection Agency's (EPA) questions and general considerations to guide the evaluation of experimental animal studies for systematic review. The primary conclusions of the panel are that one of the studies (Exxon, 1991) is not a high-quality study due to several design flaws that includes: (1) exceedance of the maximum tolerable dose in the high dose group; (2) failure to adjust feed concentrations of NMP during the lactation period, resulting in NMP doses that were 2- to 3-fold higher than nominal levels; and/or (3) underlying reproductive performance problems in the strain of rats used. For these reasons, the panel recommended that this study should not be considered for quantitative risk assessment of NMP. Exclusion of this study, and its corresponding data for male fertility and female fecundity, from the quantitative risk assessment results in a change in the identification of the most sensitive endpoint. Instead, changes in rat fetal/pup body weight, an endpoint previously selected by EPA, was identified as an appropriate basis for human health risk assessment based on a consideration of the best available science and weight of scientific evidence supported by the NMP toxicity database.

Use of biomarker data and metabolite relative potencies to support derivation of noncancer reference values based on the reproductive and developmental toxicity effects of 1,3-butadiene.

Subchronic and chronic reference values (RfVs) were derived for 1,3-butadiene (BD) based upon its ability to cause reproductive and developmental effects observed in laboratory mice and rats. Metabolism has been well-established as an important determinant of the toxicity of BD. A major challenge to human health risk assessment is presented by large quantitative species differences in the metabolism of BD, differences that should be accounted for when the rodent toxicity responses are extrapolated to humans. The methods of Fred et al. (2008)/Motwani and Törnqvist (2014) were extended and applied here to the noncancer risk assessment of using data-derived extrapolation factors to account for species differences in metabolism, as well as differences in cytotoxic potency of three BD metabolites. This approach made use of biomarker data (hemoglobin adducts) to quantify species differences in the internal doses of BD metabolites experienced in mice, rats and humans. Using these methods, the dose-response relationships in mice and rats exhibit improved concordance, and result in subchronic and chronic inhalation reference values of 29 and 10 ppm, respectively, for BD. Confidence in these reference values is considered high, based on high confidence in the key studies, medium-to-high confidence in the toxicity database, high confidence in the estimates of internal dose, and high confidence in the dose-response modeling.

An updated lymphohematopoietic and bladder cancers risk evaluation for occupational and environmental exposures to 1,3-butadiene.

EPA designated 1,3-butadiene (BD) as a high priority chemical in December 2019 and is presently performing an evaluation under the Toxic Substances Control Act (TSCA). EPA's cancer dose-response assessment for BD was published in 2002 and was primarily based on a study on workers exposed to BD in the North American synthetic Styrene-Butadiene Rubber (SBR) Industry developed by the University of Alabama at Birmingham (UAB). EPA relied upon a Poisson regression of leukemia mortality data from this cohort (hereinafter referred to as the SBR study) to estimate the cancer potency of BD. At the time, the SBR cohort included more than 15,000 male workers that were followed up through 1991. The SBR cohort has undergone multiple updates over the past two decades. Most recently, Sathiakumar et al. (2021a, b) published an update, with 18 more years of follow up in addition to approximately 5,000 female workers and updated exposure concentration estimates. Recent EPA assessments (e.g., for ethylene oxide, USEPA 2016) based on epidemiological studies use Cox proportional hazards models because they offer better control of the effect of age in cancer development and are less restrictive than Poisson regression models. Here, we develop exposure-response models using standard Cox proportional hazards regression. We explore the relationship between six endpoints (all leukemia, lymphoid leukemia, myeloid leukemia, multiple myeloma, non-Hodgkin's lymphoma, and bladder cancer) and exposures to BD using the most recent exposure metrics and the most recent update of the SBR study. After adjusting for statistically significant covariates, an upper 95% confidence level on the cancer potency based on leukemia derived herein is 0.000086 per ppm, which is approximately 1,000-fold less than EPA's (2002) estimate of 0.08 per ppm and about 10-fold less than TCEQ's (2008) estimate of 0.0011 per ppm.

Grouping of PFAS for human health risk assessment: Findings from an independent panel of experts.

An expert panel was convened to provide insight and guidance on per- and polyfluoroalkyl substances (PFAS) grouping for the purposes of protecting human health from drinking water exposures, and how risks to PFAS mixtures should be assessed. These questions were addressed through multiple rounds of blind, independent responses to charge questions, and review and comments on co-panelists responses. The experts agreed that the lack of consistent interpretations of human health risk for well-studied PFAS and the lack of information for the vast majority of PFAS present significant challenges for any mixtures risk assessment approach. Most experts agreed that "all PFAS" should not be grouped together, persistence alone is not sufficient for grouping PFAS for the purposes of assessing human health risk, and that the definition of appropriate subgroups can only be defined on a case-by-case manner. Most panelists agreed that it is inappropriate to assume equal toxicity/potency across the diverse class of PFAS. A tiered approach combining multiple lines of evidence was presented as a possible viable means for addressing PFAS that lack analytical and/or toxicological studies. Most PFAS risk assessments will need to employ assumptions that are more likely to overestimate risk than to underestimate risk, given the choice of assumptions regarding dose-response model, uncertainty factors, and exposure information.

Ethylene oxide review: characterization of total exposure via endogenous and exogenous pathways and their implications to risk assessment and risk management.

This review is intended to provide risk assessors and risk managers with a better understanding of issues associated with total exposures of human populations to ethylene oxide from endogenous and exogenous pathways. Biomonitoring of human populations and lab animals exposed to ethylene oxide has relied upon the detection of hemoglobin adducts such as 2-hydroxyethylvaline (HEV), which provides a useful measure of total exposure to ethylene oxide from all pathways. Recent biomonitoring data from CDC provide an excellent characterization of total exposure to ethylene oxide to the general U.S. population by demographic factors such as age, gender, and race as well as smoking habit, which might be comparable to previous measurements reported for humans and lab animals. The biochemical pathways including gastrointestinal (production by bacteria) and systemic (enzymatic production) pathways by which endogenous ethylene is generated and converted to ethylene oxide are described. The relative importance of endogenous pathways and exogenous pathways via ambient air or tobacco smoke was quantified based upon available data to characterize their relative importance to total exposure. Considerable variation was noted for HEV measurements in human populations, and important sources of variation for all pathways are discussed. Issues related to risk assessment and risk management of human populations exposed to ethylene oxide are provided within the context of characterizing total exposure, and data needs for supporting future risk assessment identified.

Using physiologically-based pharmacokinetic modeling to assess the efficacy of glove materials in reducing internal doses and potential hazards of N-methylpyrrolidone during paint stripping.

A refined risk assessment was conducted to evaluate the efficacy of different glove materials in reducing the potential hazards associated with using paint strippers containing N-methylpyrrolidone (NMP) under the scenarios defined by USEPA's TSCA risk assessment. Three categories of gloves were identified based on measured permeation rates for NMP: (1) minimal protection; (2) moderate protection; and (3) maximal protection. Simulations for eight acute and chronic occupational exposure scenarios identified by USEPA as having a potential hazard (i.e., margins of exposure, MOE, <30) were reassessed for each glove category using PBPK modeling to predict peak (Cmax) and cumulative (AUC) internal doses of NMP. For the acute assessment, the refined MOE values were ≥30 for half of the scenarios for gloves from the moderate protection group category, and all of the scenarios for gloves from the maximal protection category. For the chronic assessment, the refined MOE values were ≥30 for all scenarios except one for gloves from the maximal protection category. The results of this assessment indicate that: (1) the degree of protection provided by gloves from NMP permeation can vary widely depending upon the glove material, NMP formulation, and internal dose measure (with calculated glove protection factors ranging from 1.1 to 1900); and (2) NMP-containing paint strippers can be used safely when appropriate PPE are used. As such, these results can be used to support risk-reduction methods (e.g., product labeling, MSDS instructions on use of appropriate glove materials) as alternatives to banning NMP use under TSCA.

Science peer review for the 21st century: Assessing scientific consensus for decision-making while managing conflict of interests, reviewer and process bias.

Science peer review plays an important role in the advancement and acceptance of scientific information, particularly when used to support decision-making. A model for science peer review is proposed here using a large, multi-tiered case study to engage a broader segment of the scientific community to support decision making on science matters, and to incorporate many of the design advantages of the two common forms of peer review (journal peer review, science advisory panels). This peer review consisted of a two-tiered structure consisting of seven panels (five review panels in Tier 1, two review panels in Tier 2), which focused on safety data for a modified risk tobacco product (MRTP). Experts from all over the world were invited to apply to one or more positions on seven peer review panels. 66 peer reviewers were selected from available applicants using objective metrics of their expertise, and for some panels based upon a consideration of panel diversity with respect to demographic parameters (e.g., geographic region, sector of employment, years of experience). All peer reviewers participated anonymously in which a third-party auditor was used to provide independent verification of their expertise. Peer reviewers were provided electronic links to all review material which included access to publications, reports, omics data, and histopathology slides, with topic-specific panels focusing on topic-specific components of the review package. Peer reviews consisted either of single-round, or multi-round (e.g., modified Delphi) format. Peer reviewer responses to the charge questions were collected via an online survey system, and were assembled into a database. Responses in the database were subject to analyses to assess the degree of favorability (i.e., supportive of the review material), degree of consensus, reproducibility of replicate panels, hidden sources of bias, and outlier response patterns. Conclusions: By careful consideration of science peer review design elements we have shown that: 1) panel participation can be broadened to include scientists who would otherwise not participate; 2) panel diversity can be managed in an unbiased manner without adverse impacts to panel expertise; 3) results obtained from independent concurrent panels are shown to be reproducible; and 4) there are benefits of collecting input from expert panels via a structured format (i.e., survey) to support characterization of consensus, identification of hidden sources of bias, and identification of potential outlier participants.

Biomonitoring Equivalents for cyanide.

Exposure to cyanide is widespread in human populations due to a variety of natural and anthropogenic sources. The potential health risks of excess cyanide exposure are dose-dependent and include effects on the thyroid, the male reproductive system, developmental effects, neuropathies and death. Many organizations have derived exposure guideline values for cyanide, which represent maximum recommended exposure levels for inhalation and oral routes of exposure. Biomonitoring Equivalents (BEs) are estimates of the average biomarker concentrations that correspond to these reference doses. Here, we determine BE values for cyanide. The literature on the pharmacokinetics of cyanide was reviewed to identify a biomarker of exposure. Despite issues with biomarker specificity, thiocyanate (SCN-) in the urine or plasma was identified as the most practical biomarker. BE values were produced that correspond to previously published critical effect levels. These BE values range from 0.0008 to 0.8 mg/L and 0.0005-2.5 mg/L for SCN- in urine and plasma, respectively. Confidence in these BE values varies, depending on route of exposure, biomarker, and health endpoint of interest. We anticipate that these BE values will be useful for lower tier (screening level) chemical risk assessment; however due to issues with biomarker specificity and uncertainty in background levels of SCN-, this approach requires refinement to be useful at higher tiers.

Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: Ethylene oxide.

An approach is presented for ethylene oxide (EO) to derive endogenous equivalent (EE) values, which are endogenous levels normally found within the body expressed in terms of exogenous exposures. EE values can be used to support risk assessment and risk management decisions for chemicals such as EO that have both endogenous and exogenous exposure pathways. EE values were derived using a meta-analysis of data from the published literature characterizing the distribution for an EO biomarker of exposure, hemoglobin N-(2-hydroxyethyl)-valine (HEV), in unexposed populations. These levels are compared to the those reported in exposed populations (smokers, workers). Correlation between the biomarker of exposure and external exposures of EO were applied to this distribution to determine corresponding EE values, which range from 0.13 to 6.9 ppb for EO in air. These values are orders of magnitude higher than risk-based concentration values derived for EO using default methods, and are provided as a pragmatic, data-driven alternative approach to managing the potential risks from exogenous exposures to EO.

Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment.

Derivation of a No-significant-risk-level (NSRL) for dermal exposures to diethanolamine.

Diethanolamine (DEA) has been found to produce liver and kidney tumors in mice following lifetime dermal exposures. Data regarding the mode of action by which DEA produces these tumors were used to support a dose-response assessment that resulted in a no-significant-risk-level (NSRL) for dermal exposures to DEA. DEA and its metabolites are structural analogs to endogenous agents important to choline homeostasis. Sufficient information is available to support an epigenetic MOA involving the perturbation of choline homeostasis and hepatic methylation reactions in the formation of mouse liver tumors. This MOA may also apply to mouse kidney tumors, but direct measurements for key events in kidney are lacking. For both tumor types, dose-response data were pooled across four cancer bioassays conducted for DEA and DEA-containing condensates in order to provide a more robust characterization of the dose-response relationships. Doses were expressed in terms of dermally absorbed dose so that the dose-dependency and species differences in the dermal absorption of DEA were addressed. The resulting NSRL value of 3400 ug/day for dermal exposures to DEA is considered to be protective of human health for both tumor endpoints.

Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone.

The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively.

Relationships of chemical concentrations in maternal and cord blood: a review of available data.

The developing fetus is likely to be exposed to the same environmental chemicals as the mother during critical periods of growth and development. The degree of maternal-fetal transfer of chemical compounds will be affected by chemical and physical properties such as lipophilicity, protein binding, and active transport mechanisms that influence absorption and distribution in maternal tissues. However, these transfer processes are not fully understood for most environmental chemicals. This review summarizes reported data from more than 100 studies on the ratios of cord:maternal blood concentrations for a range of chemicals including brominated flame-retardant compounds, polychlorinated biphenyls (PCB), polychlorinated dibenzodioxins and dibenzofurans, organochlorine pesticides, perfluorinated compounds, polyaromatic hydrocarbons, metals, and tobacco smoke components. The studies for the chemical classes represented suggest that chemicals frequently detected in maternal blood will also be detectable in cord blood. For most chemical classes, cord blood concentrations were found to be similar to or lower than those in maternal blood, with reported cord:maternal ratios generally between 0.1 and 1. Exceptions were observed for selected brominated flame-retardant compounds, polyaromatic hydrocarbons, and some metals, for which reported ratios were consistently greater than 1. Careful interpretation of the data in a risk assessment context is required because measured concentrations of environmental chemicals in cord blood (and thus the fetus) do not necessarily imply adverse effects or risk. Guidelines and recommendations for future cord:maternal blood biomonitoring studies are discussed.

Physiologically based pharmacokinetic model for humans orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in humans. Compartments were included for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone, and a combined compartment for remaining tissues. As chronic exposure to high concentrations of Cr(VI) in drinking water cause small intestinal cancer in mice, the toxicokinetics of Cr(VI) in the upper gastrointestinal tract of rodents and humans are important for assessing internal tissue dose in risk assessment. Fasted human stomach fluid was collected and ex vivo Cr(VI) reduction studies were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pH-dependent process. For model development, toxicokinetic data for total chromium in human tissues and excreta were identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in typical humans (i.e., model predictions are within a factor of three for approximately 86% of available data). By accounting for key species differences, sources of saturable toxicokinetics, and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue of the small intestine allowing for improved health risk assessment of human populations exposed to environmentally-relevant concentrations.

Screening-level risk assessment for styrene-acrylonitrile (SAN) trimer detected in soil and groundwater.

A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment.

Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in rats and mice following long-term oral exposure. Model compartments were included for GI lumen, oral mucosa, forestomach/stomach, small intestinal mucosa (duodenum, jejunum, ileum), blood, liver, kidney, bone, and a combined compartment for remaining tissues. Data from ex vivo Cr(VI) reduction studies were used to characterize reduction of Cr(VI) in fed rodent stomach fluid as a second-order, pH-dependent process. For model development, tissue time-course data for total chromium were collected from rats and mice exposed to Cr(VI) in drinking water for 90 days at six concentrations ranging from 0.1 to 180 mg Cr(VI)/L. These data were used to supplement the tissue time-course data collected in other studies with oral administration of Cr(III) and Cr(VI), including that from recent NTP chronic bioassays. Clear species differences were identified for chromium delivery to the target tissue (small intestines), with higher concentrations achieved in mice than in rats, consistent with small intestinal tumor formation, which was observed upon chronic exposures in mice but not in rats. Erythrocyte:plasma chromium ratios suggest that Cr(VI) entered portal circulation at drinking water concentrations equal to and greater than 60 mg/L in rodents. Species differences are described for distribution of chromium to the liver and kidney, with liver:kidney ratios higher in mice than in rats. Overall, the PBPK model provides a good description of chromium toxicokinetics, with model predictions for tissue chromium within a factor of 3 for greater than 80% of measurements evaluated. The tissue data and PBPK model predictions indicate a concentration gradient in the small intestines (duodenum > jejunum > ileum), which will be useful for assessing the tumor response gradient observed in mouse small intestines in terms of target tissue dose. The rodent PBPK model presented here, when used in conjunction with a human PBPK model for Cr(VI), should provide a more robust characterization of species differences in toxicokinetic factors for assessing the potential risks associated with low-dose exposures of Cr(VI) in human populations.