Lactational PBPK modeling of bisphenol A and its analogues: ontogeny-informed estimation of internal exposure in breastfed Korean infants.

Breast milk is a route of infant exposure to bisphenol A (BPA), BPF and BPS, yet risk characterization relies on external estimated daily intake (EDI) benchmarked against guidance values varying by orders of magnitude. Because the endocrine-active moiety is the free aglycone and neonatal glucuronidation is immature, external EDI may misrepresent internal exposure. We developed an ontogeny-informed, reduced-form lactational physiologically based pharmacokinetic model converting measured milk concentrations and intake from 189 Korean mother-infant pairs into an infant internal free dose, incorporating milk free/conjugated partitioning, gut deconjugation, and age-dependent hepatic conjugation (UGT ontogeny). The adult configuration reproduced the near-complete presystemic conjugation and urinary conjugate recovery measured in controlled adult dosing, and reverse dosimetry from Ko-CHENS toddlers gave plausible intakes (median BPA 23-35 ng/kg/day). At identical dose, the infant internal free dose was amplified relative to an adult-clearance reference by a median factor of 6.1 at one month, declining to 2.2 at six months; analytically, the amplification factor equals the reciprocal of the UGT maturation fraction, so it was identical across BPA, BPF, and BPS. Adult first-pass extraction and conjugation activity at birth dominated sensitivity. External-EDI assessment therefore underweights the youngest infants, and bisphenol analogues inherit the same neonatal vulnerability.