Triple Mechanistic Convergence on MMP-9: A CDP/ACA hypothesis linking aluminum adjuvant, sorbitol, and acetaminophen to early-life neurovascular perturbation and candidate developmental Calibration

Version 1.1 — revision note Version 1.1 integrates the original MMP-9 convergence hypothesis into the Compartmental Decision Pathology (CDP) programme and its neurodevelopmental branch, Access–Calibration–Amplification (ACA). Aluminum adjuvant, parenteral sorbitol, and acetaminophen are now treated as exposure-specific Perturbations whose Access routes, intermediates, and causal roles must be demonstrated independently. MMP-9, redox imbalance, and blood–brain-barrier change are retained as candidate upstream mediators or context variables rather than being equated with developmental Calibration. The update adds an explicit ACA bridge: if the proposed early-life neurovascular convergence is experimentally confirmed, the key developmental question is whether a transient perturbation during a sensitive window alters Calibration — the mapping of intrinsic activity, instructive input, context, and prior state into persistent functional organization. The revised experimental programme therefore separates upstream factorial convergence from a post-washout, timing-sensitive Calibration test under a standardized later probe, while keeping Functional configuration and feedback Amplification as distinct, unproven layers. The three exposure arms have also been re-adjudicated. The aluminum and sorbitol pathways remain candidate, dose- and compartment-dependent modules; the acetaminophen arm no longer assumes local brain NAPQI as an established intermediate. Developmental blood–brain-barrier biology is described as functional and selectively regulated rather than simply immature or leaky. Epidemiological findings, including Andersson 2025, are used according to the question their design can answer: the Danish dose-gradient analysis constrains a simple monotonic dose–response within an overwhelmingly exposed population, but is not treated as an exposed-versus-unexposed test of the original hypothesis or as a direct test of the proposed triple interaction. Developmental regression is retained only as a possible temporal phenotype, not as an etiological subtype. Version 1.1 DOI: 10.5281/zenodo.22812990Previous version DOI: 10.5281/zenodo.19385618 Abstract Background. Early-life exposures may overlap during periods in which neural systems are still establishing functional relations. A convergence hypothesis becomes developmentally meaningful only if it distinguishes upstream exposure biology from the operation by which a developing neural compartment is organized. CDP/ACA placement. Within Compartmental Decision Pathology (CDP), this paper treats particulate aluminum adjuvant, parenteral sorbitol, and acetaminophen as candidate Perturbations. Access is invoked only where a specified causal object, route or interface measurably changes effective influence in the target compartment. Matrix metalloproteinase-9 (MMP-9), redox imbalance and blood-brain-barrier change are not Calibration by themselves; they are candidate upstream mediators, lesion/context variables, or - where they change effective availability - components of Access. The neurodevelopmental question belongs to Access-Calibration-Amplification (ACA): can a transient neurovascular perturbation during a susceptible window alter the physiological Calibration operation by which intrinsic activity, instructive input, context and prior state are mapped into persistent functional organization? Hypothesis. The three exposures may, under defined dose, route, timing and host conditions, converge on a shared neurovascular stress architecture involving MMP-9 and redox regulation. If that upstream convergence is real, it may alter the context in which developmental Calibration occurs. This paper does not claim that Calibration, a persistent Functional configuration, feedback Amplification, or any clinical phenotype has already been demonstrated. Testing strategy. The hypothesis requires two linked experimental levels. First, exposure-matched factorial experiments must establish the individual pathways, pairwise interactions, triple interaction, and causal contribution of MMP-9. Second, after the acute perturbation has resolved, an ACA bridge experiment must test whether exposure during a defined sensitive window leaves a persistent change in functional organization or response relation under a standardized later probe. A transient injury, scalar deficit, or continued toxicity would not qualify as Calibration. Conclusion. The updated model places the original MMP-9 convergence hypothesis inside a causal architecture that can fail at multiple independent layers. Its developmental significance depends not on MMP-9 elevation alone, but on whether a defined upstream perturbation is shown to alter Calibration and generate a persistent configuration that contributes to a later phenotype.