Christopher R. Kirman

Evaluation of Biomonitoring Data from the CDC National Exposure Report in a Risk Assessment Context: Perspectives across Chemicals

Background: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals [NER; Centers for Disease Control and Prevention (2012)] provide information on the presence and concentrations of > 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment–based values now allow interpretation of these biomonitoring data in a public health risk context. Objectives: We compared the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER. Methods: We identified available risk assessment–based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQs) or cancer risk estimates. Conclusions: Most analytes in the NER show HQ values of < 1; however, some (including acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides) approach or exceed HQ values of 1 or cancer risks of > 1 × 10–4 at the geometric mean or 95th percentile, suggesting exposure levels may exceed published human health benchmarks. This analysis provides for the first time a means for examining population biomonitoring data for multiple environmental chemicals in the context of the risk assessments for those chemicals. The results of these comparisons can be used to focus more detailed chemical-specific examination of the data and inform priorities for chemical risk management and research.

Estimation of safe dietary intake levels of acrylamide for humans

Acrylamide (AA), a human neurotoxicant and rat tumorigen, is produced in starchy foods when cooked. AA is also an industrial chemical used in polyacrylamide production. A safety evaluation of ingested AA by humans was conducted using a newly developed, state-of-the-art physiologically-based toxicokinetic (PBPK or PBTK) model to compare internal doses of AA and its metabolite glycidamide (GA) in humans and rats. Based on modes of action (MoA), a nonlinear dose-response approach was applied for neurotoxicity (non-genotoxicity) and carcinogenicity (mixed: genotoxicity and epigenetic MoA). Tolerable daily intake (TDI) for neurotoxicity from AA was estimated to be 40 microg/kg-day; TDIs for cancer were estimated to be 2.6 and 16 microg/kg-day based on AA or GA, respectively. Margins of exposure (MoE) were calculated for average AA consumers to be 300 and 500 based on AA and GA, respectively; for cancer, the MoE for average AA consumers was estimated to be 200 and 1200 based on AA and GA, respectively. For high consumers of AA, MoEs were somewhat less.

A chronic oral reference dose for hexavalent chromium-induced intestinal cancer

High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)‐induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg–1 day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l–1).

A Physiologically Based Pharmacokinetic Model for Acrylamide and Its Metabolite, Glycidamide, in the Rat

Acrylamide is a neurotoxicant and a multisite carcinogen in rats following chronic, high-dose exposures. In an effort to improve risk-based decisions for acrylamide (AMD) and its epoxide metabolite, glycidamide (GLY), a physiologically based pharmacokinetic (PBPK) model was developed for describing AMD and GLY kinetics in the rat. The PBPK model consists of components for both AMD and GLY. AMD is distributed within five compartments (arterial blood, venous blood, liver, lung, and all other tissues lumped together) and is linked to the GLY portion of the model via metabolism in the liver. GLY is distributed within the same five compartments. Dosing of AMD via the intravenous, intraperitoneal, or oral route of exposure is incorporated into the model structure. The model parameters include measured values for rat physiology (tissue volumes, blood flows), estimated tissue partition coefficients based on a published algorithm, and estimated values for metabolism and tissue binding based on fitting the model to tissue kinetic data from four studies. Despite gaps and limitations in the available database, a reliable description of the kinetics of AMD and GLY from existing studies was obtained using a single set of model parameters. The metabolism of AMD via cytochrome P-450 was best described using a V max of 1.6 mg/h/kg and a K m of 10 mg/L, while the metabolism of AMD via GST was described using a second-order rate constant of 0.55 L/h-mmol GSH. Similarly, the metabolism of GLY via epoxide hydrolase was best described using a V max of 1.9 mg/h/kg and a K m of 100 mg/L, while the metabolism of GLY via GST was described using a rate constant of 0.8 L/h-mmol GSH. These parameters were established based on the proportion of various metabolites found in urine. Future studies will need to focus on the collection of key data for refining model parameters for metabolism and tissue binding and for model validation, as well as for developing a similar model for humans. Completion of these additional studies will result in a validated rat and human PBPK model capable of predicting tissue doses linked to potential mechanisms of toxic effects for AMD and GLY and allow determination of scientifically defensible exposure limits that remain protective of human health.

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Abstract Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors.

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.

Hexavalent chromium reduction kinetics in rodent stomach contents

Reduction of hexavalent chromium (Cr(VI)) to trivalent chromium (Cr(III)) in the stomach prior to absorption is a well-recognized detoxification process thought to limit the toxicity of ingested Cr(VI). However, administration of high concentrations of Cr(VI) in drinking water cause mouse small intestinal tumors, and quantitative measures of Cr(VI) reduction rate and capacity for rodent stomach contents are needed for interspecies extrapolation using physiologically-based toxicokinetic (PBTK) models. Ex vivo studies using stomach contents of rats and mice were conducted to quantify Cr(VI) reduction rate and capacity for loading rates (1-400 mg Cr(VI)L(-1) stomach contents) in the range of recent bioassays. Cr(VI) reduction was measured with speciated isotope dilution mass spectrometry to quantify dynamic Cr(VI) and Cr(III) concentrations in stomach contents at select time points over 1 h. Cr(VI) reduction followed mixed second-order kinetics, dependent upon concentrations of both Cr(VI) and the native reducing agents. Approximately 16 mg Cr(VI)-equivalents of reducing capacity per L of fed stomach contents (containing gastric secretions, saliva, water and food) was found for both species. The second-order rate constants were 0.2 and 0.3 L mg(-1) h(-1) for mice and rats, respectively. These findings support that, at the doses that caused cancer in the mouse small intestine (≥ 20 mg Cr(VI)L(-1) in drinking water), the reducing capacity of stomach contents was likely exceeded. Thus, for extrapolation of target tissue dose in risk assessment, PBTK models are necessary to account for competing kinetic rates including second order capacity-limited reduction of Cr(VI) to Cr(III).

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.

Biomonitoring equivalents for DDT/DDE.

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, CAS #50-29-3) and related metabolites and degradation products DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane, CAS #72-55-90) and DDD (1,1-dichloro-2,2-bis(p-chloro-phenyl)ethane) based on both non-cancer and cancer risk assessments from the Food and Agriculture Organization/World Health Organization (FAO/WHO), the United States Environmental Protection Agency (US EPA), and other organizations. Laboratory data on distribution and toxicokinetics of DDT and metabolites and estimates of human elimination half-lives were used to estimate BE values (lipid-adjusted blood, serum, or plasma concentrations) corresponding to the various non-cancer exposure guidance values and cancer risk-specific doses. The BE values based on non-cancer risk assessments range from 5000 to 40,000ng/g lipid for the sum of DDT, DDE, and DDD. The BE values corresponding to a 1E-05 cancer risk level for DDT and DDE based on the US EPA assessment are 300 and 500ng/g lipid, respectively. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data are discussed. The BE values derived here can be used as a screening tools for evaluation of population biomonitoring data for DDT and related compounds in the context of the existing risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for DDT relative to other chemicals.

Evaluation of urinary speciated arsenic in NHANES: issues in interpretation in the context of potential inorganic arsenic exposure

Urinary dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) are among the commonly used biomarkers for inorganic arsenic (iAs) exposure, but may also arise from seafood consumption and organoarsenical pesticide applications. We examined speciated urinary arsenic data from National Health and Nutrition Examination Survey (NHANES) 2009-2010 cycle to assess potential correlations among urinary DMA, MMA, and the organic arsenic species arsenobetaine. Urinary DMA and MMA were positively associated with urinary arsenobetaine, suggesting direct exposure to these species in seafood or metabolism of organic arsenicals to these species, although the biomonitoring data do not directly identify the sources of exposure. The magnitude of association was much larger for DMA than for MMA. The secondary methylation index (SMI, ratio of urinary DMA to MMA) observed in the NHANES program likewise is much higher in persons with detected arsenobetaine than in those without, again suggesting that direct DMA exposure is co-occurring with exposure to arsenobetaine. Urinary MMA was less correlated with organic arsenic exposures than DMA and, therefore, may be a more reliable biomarker for iAs exposure in the general US population. However, given the associations between both MMA and DMA and organic arsenic species in urine, interpretations of the urinary arsenic concentrations observed in the NHANES in the context of potential arsenic exposure should be made cautiously.