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Background: Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. Objective: To evaluate a method using human in vitro data and biological modeling to calculate an acceptable exposure level through a case study on 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity (DNT). Methods: We reviewed the literature on in vitro assays studying BDE-47-induced DNT. Using the most sensitive endpoint, we derived a point of departure using a mass-balance in vitro disposition model and benchmark dose modeling for a 5% response (BMC05) in cells. We subsequently used a pharmacokinetic model of gestation and lactation to estimate administered equivalent doses leading to four different metrics of child brain concentration (i.e., average prenatal, average postnatal, average overall, and maximum concentration) equal to the point of departure. The administered equivalent doses were translated into tolerable daily intakes using uncertainty factors. Finally, we calculated biomonitoring equivalents for maternal serum and compared them to published epidemiological studies of DNT. Results: We calculated a BMC05 of 164 μg/kg of cells for BDE-47 induced alteration of differentiation in neural progenitor cells. We estimated administered equivalent doses of 0.925–3.767 μg/kg/day in mothers, and tolerable daily intakes of 0.009–0.038 μg/kg/day (composite uncertainty factor: 100). The lowest derived biomonitoring equivalent was 19.75 ng/g lipids, which was consistent with reported median (0.9–23 ng/g lipids) and geometric mean (7.02–26.9 ng/g lipids) maternal serum concentrations from epidemiological studies. Conclusion: This case study supports using in vitro data and biological modeling as a viable alternative to animal testing to derive acceptable exposure levels.

Background: Perfluorooctanoic acid (PFOA) is detected in the blood of virtually all biomonitoring study participants. Assessing health risks associated with blood PFOA levels is challenging because exposure guidance values (EGVs) are typically expressed in terms of external dose. Biomonitoring equivalents (BEs) consistent with EGVs could facilitate health-based interpretations. Objective: To i) derive BEs for serum/plasma PFOA corresponding to non-cancer EGVs of the U.S. Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR) and Health Canada, and ii) compare with PFOA concentrations from national biomonitoring surveys. Methods: Starting from EGV points of departure, we employed pharmacokinetic data/models and uncertainty factors. Points of departure in pregnant rodents (U.S. EPA 2016, ATSDR) were converted into fetus and pup serum concentrations using an animal gestation/lactation pharmacokinetic model, and equivalent human fetus and child concentrations were converted into BEs in maternal serum using a human gestation/lactation model. The point of departure in adult rodents (Health Canada) was converted into a BE using experimental data. For epidemiology-based EGVs (U.S. EPA 2023, draft), BEs were directly based on epidemiological data or derived using a human gestation/lactation pharmacokinetic model. BEs were compared with Canadian/U.S. biomonitoring data. Results: Non-cancer BEs (ng/mL) were 684 (Health Canada, 2018) or ranged from 15 to 29 (U.S. EPA, 2016), 6–10 (ATSDR, 2021) and 0.2–0.8 (U.S. EPA, 2023, draft). Ninety-fifth percentiles of serum levels from the 2018–2019 Canadian Health Measures Survey (CHMS) and the 2017–2018 National Health and Nutrition Examination Survey (NHANES) were slightly below the BE for ATSDR, and geometric means were above the non-cancer BEs for the U.S. EPA (2023, draft). Conclusion: Non-cancer BEs spanned three orders of magnitude. The lowest BEs were for EGVs based on developmental endpoints in epidemiological studies. Concentrations in Canadian/U.S. national surveys were higher than or close to BEs for the most recent non-cancer EGVs.

Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. To evaluate a method using human in vitro data and biological modeling to calculate an acceptable exposure level through a case study on 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity (DNT). We reviewed the literature on in vitro assays studying BDE-47-induced DNT. Using the most sensitive endpoint, we derived a point of departure using a mass-balance in vitro disposition model and benchmark dose modeling for a 5% response (BMC 05) in cells. We subsequently used a pharmacokinetic model of gestation and lactation to estimate administered equivalent doses leading to four different metrics of child brain concentration (i.e., average prenatal, average postnatal, average overall, and maximum concentration) equal to the point of departure. The administered equivalent doses were translated into tolerable daily intakes using uncertainty factors. Finally, we calculated biomonitoring equivalents for maternal serum and compared them to published epidemiological studies of DNT. We calculated a BMC 05 of 164 μg/kg of cells for BDE-47 induced alteration of differentiation in neural progenitor cells. We estimated administered equivalent doses of 0.925–3.767 μg/kg/day in mothers, and tolerable daily intakes of 0.009–0.038 μg/kg/day (composite uncertainty factor: 100). The lowest derived biomonitoring equivalent was 19.75 ng/g lipids, which was consistent with reported median (0.9–23 ng/g lipids) and geometric mean (7.02–26.9 ng/g lipids) maternal serum concentrations from epidemiological studies. This case study supports using in vitro data and biological modeling as a viable alternative to animal testing to derive acceptable exposure levels. [ABSTRACT FROM AUTHOR]

[Display omitted] • We derived non-cancer biomonitoring equivalents (BEs) for serum PFOA. • BEs for different exposure guidance values spanned three orders of magnitude. • BEs were lower when based on epidemiological studies than animal studies. • Lower BEs were obtained based on developmental endpoints vs. adult endpoints. • Serum PFOA levels in Canada/US were higher than or close to the lowest BEs. Perfluorooctanoic acid (PFOA) is detected in the blood of virtually all biomonitoring study participants. Assessing health risks associated with blood PFOA levels is challenging because exposure guidance values (EGVs) are typically expressed in terms of external dose. Biomonitoring equivalents (BEs) consistent with EGVs could facilitate health-based interpretations. To i) derive BEs for serum/plasma PFOA corresponding to non-cancer EGVs of the U.S. Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR) and Health Canada, and ii) compare with PFOA concentrations from national biomonitoring surveys. Starting from EGV points of departure, we employed pharmacokinetic data/models and uncertainty factors. Points of departure in pregnant rodents (U.S. EPA 2016, ATSDR) were converted into fetus and pup serum concentrations using an animal gestation/lactation pharmacokinetic model, and equivalent human fetus and child concentrations were converted into BEs in maternal serum using a human gestation/lactation model. The point of departure in adult rodents (Health Canada) was converted into a BE using experimental data. For epidemiology-based EGVs (U.S. EPA 2023, draft), BEs were directly based on epidemiological data or derived using a human gestation/lactation pharmacokinetic model. BEs were compared with Canadian/U.S. biomonitoring data. Non-cancer BEs (ng/mL) were 684 (Health Canada, 2018) or ranged from 15 to 29 (U.S. EPA, 2016), 6–10 (ATSDR, 2021) and 0.2–0.8 (U.S. EPA, 2023, draft). Ninety-fifth percentiles of serum levels from the 2018–2019 Canadian Health Measures Survey (CHMS) and the 2017–2018 National Health and Nutrition Examination Survey (NHANES) were slightly below the BE for ATSDR, and geometric means were above the non-cancer BEs for the U.S. EPA (2023, draft). Non-cancer BEs spanned three orders of magnitude. The lowest BEs were for EGVs based on developmental endpoints in epidemiological studies. Concentrations in Canadian/U.S. national surveys were higher than or close to BEs for the most recent non-cancer EGVs. [ABSTRACT FROM AUTHOR]

Background Whereas it is well established that prenatal exposure to polychlorinated biphenyls (PCBs) can disrupt children's behavior, early postnatal exposure has received relatively little attention in environmental epidemiology. Objectives To evaluate prenatal and postnatal exposures to PCB-153, a proxy of total PCB exposure, and their relation to inattention and activity in 5-year-old Inuits from the Cord Blood Monitoring Program. Methods Prenatal exposure to PCBs was informed by cord plasma PCB-153 levels. We used a validated pharmacokinetic model to estimate monthly infants' levels across the first year of life. Inattention and activity were assessed by coding of video recordings of children undergoing fine motor testing. We used multivariable linear regression to evaluate the association between prenatal and postnatal PCB-153 levels and inattention (n = 97) and activity (n = 98) at 5 years of age. Results Cord plasma PCB-153 was not associated with inattention and activity. Each interquartile range (IQR) increase in estimated infant PCB-153 levels at 2 months was associated with a 1.02% increase in the duration of inattention (95% CI: 0.04, 2.00). Statistical adjustment for the duration of breastfeeding slightly increased regression coefficients for postnatal level estimates, some of which became statistically significant for inattention (months: 2–4) and activity (months: 2–5). Conclusions Our study adds to the growing evidence of postnatal windows of development during which children are more susceptible to neurotoxicants like PCBs. [ABSTRACT FROM AUTHOR]

Abstract: We examine the balance between intake, intrinsic elimination half-lives and human body burdens measured in biomonitoring for polybrominated diphenyl ethers (PBDEs) in the North American population using the population-level pharmacokinetic model developed by Ritter et al. (2011). Empirical data are collected from two studies that made total intake estimates for the North American population for the years 2004 and 2005, and eight biomonitoring studies for the years 1992 to 2009. We assume intake of PBDEs increased exponentially to a peak in 2004, and has since exponentially declined. The model is fitted to the empirical PBDE intake and biomonitoring data on PBDE body burden using a least-square optimization method by adjusting the intake in 2004 and 2038, and the intrinsic elimination rate constants, which can be expressed as equivalent half-lives. We fit the model in two types of scenarios using different combinations of PBDE intake estimates and biomonitoring data. Our modeling results indicate that there is an inconsistency between the PBDE intake estimates and the biomonitoring data, and that the inconsistency is likely due to underestimation of population-level intake. More efforts are needed to better characterize intake rates and identify potentially-unrecognized exposure pathways. Additional age-stratified biomonitoring data, and time trends of PBDE intakes would better constrain the model and provide an improved estimation of the intrinsic elimination half-lives. [Copyright &y& Elsevier]

Abstract: Perflurooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been used for a variety of applications including fluoropolymer processing, fire-fighting foams and surface treatments since the 1950s. Both PFOS and PFOA are polyfluoroalkyl chemicals (PFCs), man-made compounds that are persistent in the environment and humans; some PFCs have shown adverse effects in laboratory animals. Here we describe the application of a simple one compartment pharmacokinetic model to estimate total intakes of PFOA and PFOS for the general population of urban areas on the east coast of Australia. Key parameters for this model include the elimination rate constants and the volume of distribution within the body. A volume of distribution was calibrated for PFOA to a value of 170ml/kgbw using data from two communities in the United States where the residents'' serum concentrations could be assumed to result primarily from a known and characterized source, drinking water contaminated with PFOA by a single fluoropolymer manufacturing facility. For PFOS, a value of 230ml/kgbw was used, based on adjustment of the PFOA value. Applying measured Australian serum data to the model gave mean±standard deviation intake estimates of PFOA of 1.6±0.3ng/kgbw/day for males and females >12years of age combined based on samples collected in 2002–2003 and 1.3±0.2ng/kg bw/day based on samples collected in 2006–2007. Mean intakes of PFOS were 2.7±0.5ng/kgbw/day for males and females >12years of age combined based on samples collected in 2002–2003, and 2.4±0.5ng/kgbw/day for the 2006–2007 samples. ANOVA analysis was run for PFOA intake and demonstrated significant differences by age group (p =0.03), sex (p =0.001) and date of collection (p <0.001). Estimated intake rates were highest in those aged >60years, higher in males compared to females, and higher in 2002–2003 compared to 2006–2007. The same results were seen for PFOS intake with significant differences by age group (p <0.001), sex (p =0.001) and date of collection (p =0.016). [Copyright &y& Elsevier]