Incorporating new approach methods (NAMs) data in dose–response assessments: The future is now!

Journal of Toxicology and Environmental Health Part B, Год журнала: 2024, Номер unknown, С. 1 - 35

Опубликована: Окт. 10, 2024

Regulatory dose–response assessments traditionally rely on in vivo data and default assumptions. New Approach Methods (NAMs) present considerable opportunities to both augment traditional accelerate the evaluation of new/data-poor chemicals. This review aimed determine potential utilization NAMs through a unified conceptual framework that compartmentalizes derivation toxicity values into five sequential Key Dose–response Modules (KDMs): (1) point-of-departure (POD) determination, (2) test system-to-human (e.g. inter-species) toxicokinetics (3) toxicodynamics, (4) human population (intra-species) variability (5) toxicokinetics. After using several "traditional" dose-response illustrate this framework, is presented where existing NAMs, including silico, vitro, approaches, might be applied across KDMs. Further, false dichotomy between NAMs-derived sources broken down by organizing matrix each KDM has Tiers increasing precision confidence: Tier 0: Default/generic values, 1: Computational predictions, 2: Surrogate measurements, 3: Direct measurements. These findings demonstrated although many publications promote use KDMs for POD determination toxicokinetics, proposed reveals additional immediate integrated other critical needs were identified developing improve vitro dosimetry quantify system toxicodynamics. Overall, broadening integration steps assessment promises yield higher throughput, less animal-dependent, more science-based protecting health.

Язык: Английский

---

Invited Perspective: Uneven Progress Addressing Population Variability in Human Health Risk Assessment

Environmental Health Perspectives, Год журнала: 2024, Номер 132(3)

Опубликована: Март 1, 2024

Язык: Английский

---

The mediating role of AKT/ERK/JNK signaling on the malignant phenotype of microcystin-LR in gastric adenocarcinoma cells

Food and Chemical Toxicology, Год журнала: 2023, Номер 182, С. 114174 - 114174

Опубликована: Ноя. 8, 2023

Язык: Английский

---

Personalized mixture toxicity testing: A proof-of-principle in vitro study evaluating the steroidogenic effects of reconstructed contaminant mixtures measured in blood of individual adults

Environment International, Год журнала: 2024, Номер 192, С. 108991 - 108991

Опубликована: Авг. 30, 2024

Chemical risk assessments typically focus on single substances, often overlooking real-world co-exposures to chemical mixtures. Mixture toxicology studies using representative mixtures can reveal potential interactions, but these do not account for the unique profiles that occur in blood of diverse individuals. Here we used H295R steroidogenesis assay screen personalized 24 persistent organic pollutants (POPs) cytotoxicity and endocrine disruption. Each mixture was reconstructed at a human exposure relevant concentration (1×), as well 10- 100-fold higher (10×, 100×) by acoustic liquid handling based measured concentrations Swedish cohort. Among twelve tested, nine decreased cell viability 4-18%, primarily highest concentration. While median maximum whole study population induced no measurable effects any concentration, from an individual with lowest total POPs only affected estradiol synthesis (35% increase 100× concentration). Mixtures levels three different individuals stimulated testosterone 1× (11-15%) 10× (12-16%), This proof-of-principle toxicity illustrates population-based may adequately toxicological risks posed It highlights importance testing range explore interactions non-monotonic effects. Further contaminant could improve assessment advance understanding health, exposome data become increasingly available.

Язык: Английский

---

Dosing Methods to Enable Cell-Based In Vitro Testing of Complex Substances: A Case Study with a PAH Mixture

Toxics, Год журнала: 2022, Номер 11(1), С. 19 - 19

Опубликована: Дек. 26, 2022

Cell-based testing of multi-constituent substances and mixtures for their potential adverse health effects is difficult due to complex composition physical-chemical characteristics. Various extraction methods are typically used enable studies in vitro; however, a limited number solvents biocompatible with vitro the extracts may not fully represent original test article's composition. While dosing "difficult-to-test" aquatic toxicity well defined widely used, they largely unsuited small-volume (100 microliters or less) mammalian cells. Therefore, we aimed evaluate suitability various scaled-down high-throughput by using mixture polycyclic aromatic hydrocarbons (PAH). Specifically, compared passive via silicone micro-O-rings, cell culture media-accommodated fraction, traditional solvent (dimethyl sulfoxide) procedures. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was kinetics PAH absorption as recovery extent protein binding media without cells each method. Bioavailability from different also evaluated characterizing cytotoxicity EA.hy926 HepG2 human lines. Of tested methods, accommodated fraction (MAF) determined be most appropriate method cell-based PAH-containing mixtures. This conclusion based on observation that highest starting materials can delivered approach into thus concentration-response testing.

Язык: Английский

---

New approach methodologies to address population variability and susceptibility

Human Genomics, Год журнала: 2023, Номер 17(1)

Опубликована: Июнь 28, 2023

Язык: Английский

---