8 extrapolation modeling. The NCR vision also describes a paradigm shift away from a focus on identifying adverse eﬀects observed in experimental animals at high doses toward identifying and avoiding biologically signiﬁcant per- turbations of key toxicity pathways [59]. The identiﬁcation of transition points between normal function and exposures that lead to accumulation and eﬀects of an agent, as well as a consideration of the adaptive changes that respond to initial perturbations and function to maintain homeostasis, is a key to the NRC vision (see [58, Figure 2.2]). In our opinion, signiﬁcant changes in tissue manganese concentra- tions represent a critical early step in the development of manganese neurotoxicity. Importantly, this work has iden- tiﬁed a dose-dependent transition in manganese kinetics, which is a point where there is a change in the relationship of tissue accumulation as a function of dose [60, 61]. The pharmacokinetic data and PBPK modeling have shown that background tissue manganese levels are well maintained at low to moderate exposure levels, due to the existence of homeostatic control mechanisms, such as increased biliary manganese excretion, that serve to regulate tissue levels. Only once those mechanisms are overwhelmed do tissue levels start to increase signiﬁcantly. Due to the existence of this dose-dependent transition, only roughly one order of magnitude separates the point of departures on which previous manganese risk assessments are based and a level of exposure at which no signiﬁcant changes in Mn tissue concentration is predicted to occur in target tissues. This may indicate that large uncertainty factors are not necessary when extrapolating high-dose occupational exposure levels to low environmental exposure levels for the general population for an essential element such as Mn. The human PBPK models for Mn that emerged from this program can be used to further analyze the relationship between exposure and target tissue concentration and provide a consistent dose-response relationship for the eﬀects of Mn regardless of exposure route and duration [43]. The models can be used to extrapolate to lower exposures to determine a concentration at which no signiﬁcant eﬀect on brain concentrations would be expected compared to normal variation. The human PBPK model can consider all life stages (fetuses, neonates, adults, and old age), both genders, pregnancy, and form of Mn. This model will be a critical tool for the quantitative risk assessment of environmental and occupational exposures to Mn. The model and these applications are discussed in more detail in Part 2 of this series [2]. Acknowledgments The authors would like to thank Dr. William K. Boyes for generously providing Figure 1 and contributing to helpful discussions regarding this paper. 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