TY - JOUR
T1 - Using in vitro data to derive acceptable exposure levels
T2 - A case study on PBDE developmental neurotoxicity
AU - Bloch, Sherri
AU - Lévêque, Laura
AU - Hertz-Picciotto, Irva
AU - Puschner, Birgit
AU - Fritsche, Ellen
AU - Klose, Jördis
AU - I. Kramer, Nynke
AU - Bouchard, Maryse F.
AU - Chandrasekera, P.
AU - Verner, Marc André
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - Biomonitoring equivalent
KW - In vitro toxicology testing
KW - Mass-balance modeling
KW - Pharmacokinetic modeling
KW - Risk assessment
KW - Tolerable daily intake
U2 - 10.1016/j.envint.2023.108411
DO - 10.1016/j.envint.2023.108411
M3 - Article
C2 - 38217900
AN - SCOPUS:85182503353
SN - 0160-4120
VL - 183
JO - Environment International
JF - Environment International
M1 - 108411
ER -