Biomonitoring Equivalents for ethylene thiourea.

Ethylene thiourea, or ETU, is used in the rubber industry and is a degradation product and impurity in some fungicides. The general public may be exposed to low concentrations of residues of ETU in a variety of ways, including food treated with ethylene bis-dithiocarbamate (EBDC) fungicides or migration from rubber products. Biomonitoring of ETU in urine is useful for an assessment of integrated exposures to ETU across different sources and routes of exposure. In this evaluation, we review available health-based risk assessments and toxicological reference values (TRVs) for ETU and derive Biomonitoring Equivalent (BE) values for interpretation of population biomonitoring data. BEs were derived based on existing TRVs derived by Health Canada, yielding a BE of 27 µg of total ETU/L in urine associated with the Acceptable Daily Intake (ADI) and 6.7 µg/L associated with a 1e-6 cancer risk. These BEs are based on an analytical method that involves a digestion step to liberate conjugated ETU, thus producing 'total' ETU in urine. The BE values derived in this manuscript can serve as a guide to help public health officials and regulators interpret population based ETU biomonitoring data in a public health risk context.

Weight of evidence evaluation for chemical-induced immunotoxicity for PFOA and PFOS: findings from an independent panel of experts.

Immunotoxicity is the critical endpoint used by some regulatory agencies to establish toxicity values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, the hypothesis that exposure to certain per- and polyfluoroalkyl substances (PFAS) causes immune dysregulation is subject to much debate. An independent, international expert panel was engaged utilizing methods to reduce bias and "groupthink". The panel concluded there is moderate evidence that PFOS and PFOA are immunotoxic, based primarily on evidence from animal data. However, species concordance and human relevance cannot be well established due to data limitations. The panel recommended additional testing that includes longer-term exposures, evaluates both genders, includes other species of animals, tests lower dose levels, assesses more complete measures of immune responses, and elucidates the mechanism of action. Panel members agreed that the Faroe Islands cohort data should not be used as the primary basis for deriving PFAS risk assessment values. The panel agreed that vaccine antibody titer is not useful as a stand-alone metric for risk assessment. Instead, PFOA and PFOS toxicity values should rely on multiple high-quality studies, which are currently not available for immune suppression. The panel concluded that the available PFAS immune epidemiology studies suffer from weaknesses in study design that preclude their use, whereas available animal toxicity studies provide comprehensive dataset to derive points of departure (PODs) for non-immune endpoints. The panel recommends accounting for potential PFAS immunotoxicity by applying a database uncertainty factor to POD values derived from animal studies for other more robustly supported critical effects.

Biomonitoring Equivalents for N,N-Diethyl-meta-toluamide (DEET).

N,N-Diethyl-meta-toluamide (DEET) is widely used as an effective mosquito and tick repellent. DEET is absorbed systemically after applications to skin. Once absorbed, DEET is rapidly metabolized with the predominant metabolite being m-dimethylaminocarbonyl benzoic acid (DBA). DEET and metabolites are predominantly excreted in urine after being absorbed systemically. Exposures to DEET are typically biomonitored via measures of DEET and DBA in urine. In this evaluation, we review available health-based risk assessments and toxicological reference values (TRVs) for DEET and derive Biomonitoring Equivalent (BE) values for interpretation of population biomonitoring data. BEs were derived based on existing TRVs derived by Health Canada, yielding 38 and 23 mg/L DBA in urine for adults and 57 and 34 mg/L DBA in urine in children for the acute oral and intermediate dermal TRVs, respectively. The BEs for unchanged DEET in urine are 21 and 12 mg/L in adults and 4.5 and 2.7 mg/L in children for the acute oral and intermediate dermal TRVs. The BE values derived in this manuscript can serve as a guide to help public health officials and regulators interpret population based DEET biomonitoring data in a public health risk context.

Biomonitoring Equivalents for glyphosate.

One of the most widely used herbicides worldwide, glyphosate is registered for use in many agricultural and non-agricultural settings. Accordingly, regulatory authorities develop toxicology reference values (TRVs) to conduct risk assessments for potential exposures. Exposures to glyphosate are typically biomonitored via measures of glyphosate in urine. However, measured concentrations of glyphosate in urine, with units mg/L urine, cannot be directly interpreted using the available TRVs as they are presented in terms of daily intake levels (e.g. mg/kg-bw per day). In this evaluation, we review available health-based risk assessments and TRVs for glyphosate and derive Biomonitoring Equivalent (BE) values for interpretation of population biomonitoring data. Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, human milk, etc.) that is consistent with an existing health-based TRVs such as a reference dose (RfD) or tolerable daily intake (TDI). The BE values derived in this manuscript are screening values that can help public health officials and regulators interpret glyphosate biomonitoring data.

Best practices for exposure model peer review - A SciPinion advisory panel report.

The extent and rigor of peer review that a model undergoes during and after development influences the confidence of users and managers in model predictions. A process for determining the breadth and depth of peer review of exposure models was developed with input from a panel of exposure-modeling experts. This included consideration of the tiers and types of models (e.g., screening, deterministic, probabilistic, etc.). The experts recommended specific criteria be considered when evaluating the degree to which a model has been peer reviewed, including quality of documentation and the model peer review process (e.g., internal review with a regulatory agency by subject matter experts, expert review reports, formal Scientific Advisory Panels, and journal peer review). In addition, because the determination of the confidence level for an exposure model's predictions is related to the degree of evaluation the model has undergone, irrespective of peer review, the experts recommended the approach include judging the degree of model rigor using a set of specific criteria: (1) nature and quality of input data, (2) model verification, (3) model corroboration, and (4) model evaluation. Other key areas considered by the experts included recommendations for addressing model uncertainty and sensitivity, defining the model domain of applicability, and flags for when a model is used outside its domain of applicability. The findings of this expert engagement will help developers as well as users of exposure models have greater confidence in their application and yield greater transparency in the evaluation and peer review of exposure models.

Derivation of Biomonitoring Equivalents for aluminium for the interpretation of population-level biomonitoring data.

Aluminium is widely used in many consumer products, however the primary source of aluminium exposure to the Canadian general population is through food. Aluminium can cause neurotoxicity and reproductive toxicity at elevated exposure levels. Health-based exposure guidance values have been established for oral exposure to aluminium, including a Minimal Risk Level (MRL) by the Agency for Toxic Substances and Disease Registry (ATSDR), a Provincial Tolerable Weekly Intake (PTWI) by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and a Tolerable Weekly Intake (TWI) by the European Food Safety Authority (EFSA). Aluminium concentration in blood and urine can be used as a tool for exposure characterization in a population. A pharmacokinetic (PK) model was developed based on human dosing data to derive blood Biomonitoring Equivalents (BEs), whereas a mass balance approach was used to derive urine BEs for the above guidance values. The BEs for blood for daily intake consistent with the MRL, PTWI and TWI were 18, 16 and 8 µg/L, respectively. BEs for urine for the same guidance values were 137, 123 and 57 µg/L, respectively. The derived BEs may be useful in interpreting population-level biomonitoring data in a health risk context and thereby screening and prioritizing substances for human health risk assessment and risk management.

Peer review of a cancer weight of evidence assessment based on updated toxicokinetics, genotoxicity, and carcinogenicity data for 1,3-dichloropropene using a blinded, virtual panel of experts.

A cancer weight of evidence (WOE) analysis based on updated toxicokinetics, genotoxicity, and carcinogenicity data for 1,3-dichloropropene was peer reviewed by a panel of experts. Historically, 1,3-dichloropropene has been classified in the U.S. as "likely to be carcinogenic to humans" via oral and inhalation exposure routes based upon the results of rodent cancer bioassays conducted in the 1980s. Contemporary studies led the authors of the WOE analysis to conclude that the currently manufactured form of 1,3-dichloropropene is not mutagenic and not carcinogenic below certain doses, pointing to a threshold-based approach for cancer risk assessment. SciPinion conducted a peer review of the WOE analysis using methods for assembling and managing blinded expert panels that maximize expertise while minimizing potential selection/participation bias. The process was implemented through a web-based application that poses a series of questions soliciting the experts' scientific opinions and observations about specific topics. The goal of the peer review was to have experts provide conclusions about the WOE for carcinogenicity classification of 1,3-dichloropropene, identify potential data gaps, and evaluate the validity of a threshold-based risk assessment for 1,3-dichloropropene. Based on a robust peer review of the current scientific information, a cancer WOE classification of "not likely to be carcinogenic to humans" is best supported for 1,3-dichloropropene. This conclusion is reached with a high degree of consensus (consensus score = 0.92) across expert panel members.

Derivation of biomonitoring equivalents (BE values) for bismuth.

Bismuth (Bi) is a natural element present in the environmental media. Bismuth has been used medicinally for centuries, specifically for the treatment of gastrointestinal (GI) disorders. Although bismuth toxicity is rare in humans, an outbreak of bismuth-induced neurotoxicity was reported in France and Australia in the mid-1970s. The primary source of bismuth exposure in the general population is via food. US FDA (2019) estimated recommended daily intake (RDI) for bismuth as 848 mg bismuth/day (12.1 mg Bi/kg-d assuming a body weight of 70 kg) for GI tract disorders. Exposures to bismuth can be quantified by measuring concentrations in blood and urine. Biomonitoring equivalents (BEs) were derived based on US FDA's RDI as a tool for interpretation of population-level biomonitoring data. A regression between steady state plasma concentrations and oral intakes was used to derive plasma BEs. A whole blood: plasma partitioning coefficient of 0.6 was used to convert plasma BE into whole blood BE. A mass balance equation with a urinary excretion fraction of 0.0003 was used to derive urinary BE. The BE values associated with US FDA's RDI for plasma, whole blood and urine were 8.0, 4.8 and 0.18 µg/L, respectively. These BE values together with bismuth biomonitoring data may be used in screening and prioritization of health risk assessment of bismuth in the general population.

Biomonitoring Equivalents (BEs) for tetrabromobisphenol A.

Tetrabromobisphenol A (TBBPA) is a flame retardant used in a variety of products, including epoxy and polycarbonate resins. Relevant exposure to TBBPA has been assessed by measuring TBBPA in the blood of humans. Here, we derive Biomonitoring Equivalents (BEs) for TBBPA to interpret these, and future biomonitoring results for TBBPA in humans. The available toxicity risk values (TRVs) for TBBPA were all based on toxicology studies in rats. Several studies have been conducted in which TBBPA in blood of rats were measured following controlled oral doses of TBBPA. These data provide a robust relationship from which to derive BEs. BEs of 5.6 and 13.0 µg total TBBPA/L plasma were calculated for available cancer and non-cancer TRVs, respectively. Several studies have measured TBBPA in serum, with median concentrations less than 0.1 µg/L, indicating considerable margins of safety (MOS) for TBBPA based on the currently available biomonitoring studies.

Extrapolation of plasma clearance to understand species differences in toxicokinetics of bisphenol A.

1. Understanding species differences in the toxicokinetics of bisphenol A (BPA) is central to setting acceptable exposure limits for human exposures to BPA. BPA toxicokinetics have been well studied, with controlled oral dosing studies in several species and across a wide dose range. 2. We analyzed the available toxicokinetic data for BPA following oral dosing to assess potential species differences and dose dependencies. BPA is rapidly conjugated and detoxified in all species. The toxicokinetics of BPA can be well described using non-compartmental analyses. 3. Several studies measured free (unconjugated) BPA in blood and reported area under the curve (AUC) of free BPA in blood of mice, rats, monkeys, chimpanzees and humans following controlled oral doses. Extrinsic clearance was calculated and analyzed across species and dose using allometric scaling. 4. The results indicate free BPA clearance is well described using allometric scaling with high correlation coefficients across all species and doses up to 10 mg/kg. The results indicate a human equivalent dose factor (HEDf) of 0.9 is appropriate for extrapolating a point of departure from mice and rats to a human equivalent dose (HED), thereby replacing default uncertainty factors for animal to human toxicokinetics.

Biomonitoring Equivalents for interpretation of urinary iodine.

Iodine is an essential nutrient whose deficiency or excess exposure can cause adverse health effects. The primary sources of iodine exposure in the general population are iodized salt, dairy products, bread and sea food. Urinary iodine concentrations (UIC) have been measured by Canadian Health Measures Survey (CHMS) and US National Health and Nutrition Examination Survey (NHANES). The Institute of Medicine (IOM), the US Agency for Toxic Substances and Disease Registry (ATSDR) and World Health Organization (WHO) have established exposure guidance values for nutrition (IOM Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), WHO Recommended Nutrient Intake (RNI)) and toxicity (IOM Tolerable Upper Intake Level (UL); ATSDR Minimal Risk Level (MRL), WHO International Programme on Chemical Safety (IPCS) Tolerable Daily Intake (TDI)). Using a urinary excretion fraction of 0.9, Biomonitoring Equivalents (BE) for the EAR, RDA, UL and MRL were derived for adults (60, 100, 730 and 450 µg/L, respectively) and children (50, 80, 580 and 360 µg/L, respectively). The population median UIC values from NHANES and CHMS for adults (140-181, 122-126 µg/L, respectively) and children (232, 189 µg/L, respectively) were above the criteria for assessing iodine nutrition, indicating that US and Canadian populations are likely to have adequate population iodine nutrition. The median UIC from NHANES and CHMS do not exceed BE values derived from exposure guidance values for toxicity.

Screening-level Biomonitoring Equivalents for tiered interpretation of urinary 3-phenoxybenzoic acid (3-PBA) in a risk assessment context.

3-Phenoxybenzoic acid (3-PBA) is a common metabolite of several pyrethroid pesticides of differing potency and also occurs as a residue in foods resulting from environmental degradation of parent pyrethroid compounds. Thus, 3-PBA in urine is not a specific biomarker of exposure to a particular pyrethroid. However, an approach derived from the use of Biomonitoring Equivalents (BEs) can be used to estimate a conservative initial screening value for a tiered assessment of population data on 3-PBA in urine. A conservative generic urinary excretion fraction for 3-PBA was estimated from data for five pyrethroid compounds with human data. Estimated steady-state urinary 3-PBA concentrations associated with reference doses and acceptable daily intakes for each of the nine compounds ranged from 1.7 µg/L for cyhalothrin and deltamethrin to 520 µg/L for permethrin. The lower value can be used as a highly conservative Tier 1 screening value for assessment of population urinary 3-PBA data. A second tier screening value of 87 µg/L was derived based on weighting by relative exposure estimates for the different pyrethroid compounds, to be applied as part of the data evaluation process if biomonitoring data exceed the Tier 1 value. These BE values are most appropriately used to evaluate the central tendency of population biomarker concentration data in a risk assessment context. The provisional BEs were compared to available national biomonitoring data from the US and Canada.

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin-of-exposure values for hexavalent chromium.

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg-1  day-1 , is based on a no-observable-adverse-effect-level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as "low." A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non-neoplastic lesions from the 2 year cancer bioassay were modeled in a three-step process. First, a rodent physiological-based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg-1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)-induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non-cancer endpoints; all RfD values ranged 0.003-0.02 mg kg-1  day-1 . The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg-1  day-1 , the confidence is greatly improved due to the use of a 2-year bioassay, mechanistic data, PBPK models and benchmark dose modeling.

Risk assessment and Biomonitoring Equivalent for 2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB) and tetrabromobenzoic acid (TBBA).

2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB) is used as a flame retardant. Biomonitoring for TBB exposures include the metabolite, tetrabromobenzoic acid (TBBA), in urine. We derived a Reference Dose (RfD) for TBB and a Biomonitoring Equivalent (BE) for TBBA in urine. Three longer-term studies of oral gavage dosing of a commercial mixture BZ-54 (which includes 70% TBB) in rats were evaluated for deriving the RfD. The 95% lower confidence limits on the BMD associated with a 1 SD change from the mean (BDMLSD) values ranged from 77 to 134 mg/kg-day. The mean BMDLSD value of 91 mg/kg-day for maternal body weight changes was selected as the appropriate point of departure (POD), corresponding to a human equivalent dose (PODHEC) of 25 mg/kg-day. A total composite uncertainty factor (UF) of 300 yields an RfD of 0.08 mg/kg-day. A urinary mass excretion fraction (Fue) of 0.6 for TBBA following oral doses of TBB in rats was used to calculate BEs for TBBA in urine of 2.5 mg/L and 2.5 mg/g cr. Mean (5.3 × 10-6 mg/L) and maximum (340 × 10-6 mg/L) levels of TBBA measured in urine from human volunteers reported in the literature indicates margins of safety (MOS) are approximately 450,000 and 7,000, respectively.

Reduction of hexavalent chromium by fasted and fed human gastric fluid. II. Ex vivo gastric reduction modeling.

To extend previous models of hexavalent chromium [Cr(VI)] reduction by gastric fluid (GF), ex vivo experiments were conducted to address data gaps and limitations identified with respect to (1) GF dilution in the model; (2) reduction of Cr(VI) in fed human GF samples; (3) the number of Cr(VI) reduction pools present in human GF under fed, fasted, and proton pump inhibitor (PPI)-use conditions; and (4) an appropriate form for the pH-dependence of Cr(VI) reduction rate constants. Rates and capacities of Cr(VI) reduction were characterized in gastric contents from fed and fasted volunteers, and from fasted pre-operative patients treated with PPIs. Reduction capacities were first estimated over a 4-h reduction period. Once reduction capacity was established, a dual-spike approach was used in speciated isotope dilution mass spectrometry analyses to characterize the concentration-dependence of the 2nd order reduction rate constants. These data, when combined with previously collected data, were well described by a three-pool model (pool 1 = fast reaction with low capacity; pool 2 = slow reaction with higher capacity; pool 3 = very slow reaction with higher capacity) using pH-dependent rate constants characterized by a piecewise, log-linear relationship. These data indicate that human gastric samples, like those collected from rats and mice, contain multiple pools of reducing agents, and low concentrations of Cr(VI) (<0.7 mg/L) are reduced more rapidly than high concentrations. The data and revised modeling results herein provide improved characterization of Cr(VI) gastric reduction kinetics, critical for Cr(VI) pharmacokinetic modeling and human health risk assessment.

Biomonitoring Equivalents for molybdenum.

Molybdenum is an essential trace element for mammalian, plant, and other animal systems. The Institute of Medicine (IOM) has established an Estimated Average Requirement (EAR) to assure sufficient molybdenum intakes for human populations; however excessive exposures can cause toxicity. As a result, several agencies have established exposure guidance values to protect against molybdenum toxicity, including a Reference Dose (RfD), Tolerable Daily Intake (TDI) and a Tolerable Upper Intake Level (UL). Biomonitoring for molybdenum in blood or urine in the general population is being conducted by the Canadian Health Measures Survey (CHMS) and the U.S. National Health and Nutrition Examination Survey (NHANES). Using pharmacokinetic data from controlled human dosing studies, Biomonitoring Equivalents (BEs) were calculated for molybdenum in plasma, whole blood, and urine associated with exposure guidance values set to protect against both nutritional deficits and toxicity. The BEEAR values in plasma, whole blood and urine are 0.5, 0.45 and 22 µg/L, respectively. The BEs associated with toxicity range from 0.9 to 31 µg/L in plasma, 0.8-28 µg/L in whole blood and 200-7500 µg/L in urine. These values can be used to interpret molybdenum biomonitoring data from a nutritional and toxicity perspective.

Implementing a framework for integrating toxicokinetics into human health risk assessment for agrochemicals.

A strategic and comprehensive program in which toxicokinetic (TK) measurements are made for all agrochemicals undergoing toxicity testing (both new compounds and compounds already registered for use) is described. This approach provides the data to more accurately assess the toxicokinetics of agrochemicals and their metabolites in laboratory animals and humans. Having this knowledge provides the ability to conduct more insightful toxicity studies, refine and interpret exposure assessments and reduce uncertainty in risk assessments. By developing a better understanding of TK across species, including humans via in vitro metabolism studies, any differences across species in TK can be identified early and the most relevant species can be selected for toxicity tests. It also provides the ability to identify any non-linearities in TK as a function of dose, which in turn can be used to identify a kinetically derived maximum dose (KMD) and avoid dosing inappropriately outside of the kinetic linear range. Measuring TK in key life stages also helps to identify changes in ADME parameters from in utero to adults. A robust TK database can also be used to set internal concentration based "Reference Concentrations" and Biomonitoring Equivalents (BE), and support selection of Chemical Specific Adjustment Factors (CSAF). All of these factors support the reduction of uncertainty throughout the entire risk assessment process. This paper outlines how a TK research strategy can be integrated into new agrochemical toxicity testing programs, together with a proposed Framework for future use.

California biomonitoring data: Comparison to NHANES and interpretation in a risk assessment context.

The California Environmental Biomonitoring Program (also known as Biomonitoring California) has been generating human biomonitoring data and releasing it via their website. The current Biomonitoring California program is a collection of smaller studies, targeting specific populations (e.g., fire fighters, breast cancer patients and controls, etc.). In this paper we compare the results from Biomonitoring California with those from the US National Health and Nutrition Examination Survey (NHANES). We also compare California's results with Biomonitoring Equivalents (BEs) for those compounds for which BEs exist. In general, the results from California are consistent with the biomonitoring levels found across the US via NHANES. A few notable exceptions are levels of flame retardants amongst fire fighters in California, which are higher than observed in NHANES and some persistent organic chemicals amongst a study of breast cancer patients and controls in California which are higher than in the overall adult population in NHANES. The higher levels amongst fire fighters may be a result of fire fighters being exposed to higher levels of flame retardants while fighting fires. The higher levels of the persistent organics amongst breast cancer patients is likely due to this population being older than the mean age in NHANES. Comparisons to BEs indicate that biomonitoring levels in California are all consistently below levels of concern as established by regulatory agencies.