Statistical approach for ...a test chemical is considered to be positive... in regulatory toxicology: Trend and pairwise tests

Hothorn, L. A.

doi:10.1101/858571

Home/Archive/bioRxiv

bioRxiv · 10.1101/858571

Statistical approach for ...a test chemical is considered to be positive... in regulatory toxicology: Trend and pairwise tests

Hothorn, L. A.

View original source ↗Export metadata ↓

Abstract

In regulatory toxicology an outcome is claimed positive when both a trend is significant and any pairwise test against control. Two statistical approaches are proposed: a joint Dunnett and Williams test (assuming the dose as a qualitative factor) and a joint test of the Tukey regression test and Dunnett test (assuming the dose as a quantitative covariate). Related R software is available.

Explore related subjects

pharmacology and toxicology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Hothorn, L. A.. 2019-11-29. Statistical approach for ...a test chemical is considered to be positive... in regulatory toxicology: Trend and pairwise tests. https://doi.org/10.1101/858571

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Mathematical model of phenotypic plasticity predicts interconversion is a drug target for neuroblastoma.

Neuroblastoma is a paediatric cancer arising from the sympathetic nervous system as neural crest cells, made up of noradrenergic (NOR/ADRN/N), mesenchymal like (MES/S), and intermediate (I-type/I) cell types. These cells can interconvert between types, contributing to treatment resistance and relapse. We developed a mathematical model to investigate how interconversion patterns affect the efficacy of phenotype-specific inhibitors. We used three ordinary differential equations to describe the dynamics of the three populations, including logistic growth, interconversion, and drug-induced death. Of the 64 possible interconversion patterns, five reduced the target population: two for N cells and three for S cells. N targeting patterns were more effective with higher interconversion rates, while mesenchymal targeting patterns were more effective with lower interconversion rates. Stability analysis revealed that natural tumour growth was always unstable, but during treatment, N-suppressing patterns combined with an S inhibitor gave the most consistently stable origin. Testing multi-stage and cyclic treatment schedules revealed that N-suppressing patterns with an S inhibitor, followed by an S-suppressing pattern with an N inhibitor, achieved more reliable remission. Three of the five patterns of interest correspond to reported biological plausibility, and known compounds exist to induce most of the required transitions, supporting the clinical relevance of these strategies for improving neuroblastoma treatment outcomes.

pharmacology and toxicology↗

bioRxiv2026

Organism-dependent ecotoxicological effects of transition metal-containing layered double hydroxides

Due to low environmental stability of certain molecule classes, such as phytohormones and RNA interference, layered double hydroxides (LDHs) have been investigated as nanocarriers capable of protecting and transporting molecules of interest in natural systems. Herein, the ecotoxicological effects of LDH nanoparticles composed by different transition metals (Al-Ni, Al-Co, and Al-Cu) were evaluated in maize (Zea mays), tomato (Lycopersicum esculentum), and the nematode Caenorhabditis elegans, two important crops and one soil organism found in agricultural systems. Plants were exposed to the nanoparticles through foliar spraying (5, 50, and 500 ug/mL), and physiological parameters were evaluated. In C. elegans, lethality, locomotion, larval development, and body length were analyzed. The nanoparticles exhibited high colloidal stability and characteristic lamellar morphology. The results demonstrated low phytotoxicity for all formulations, without significant changes in photochemical activity, effective quantum yield of photosystem II (psi-PSII), stomatal conductance (gs), and chlorophyll index (Chl a+b; ICF) in plants. In contrast, C. elegans exhibited greater sensitivity, showing reduced motility, developmental delay, and decreased body length, although mortality remained below 12% under all evaluated conditions. Toxicity was dependent on the metallic composition, following the order Al-Cu > Al-Ni > Al-Co. Collectively, the results indicate that LDHs exhibit high compatibility with those two crops but may cause sublethal effects in soil organisms. These findings highlight the importance of multispecies ecotoxicological assessments for the safe development of nanocarriers intended for agricultural applications.

pharmacology and toxicology↗

bioRxiv2026

Aging, HIV Status, and Sex Differentially Influence Antiretroviral Therapy Disposition Pathways in Rectosigmoid Tissue and Peripheral Blood Mononuclear Cells

People living with human immunodeficiency virus (HIV) are increasingly surviving into older age due to the effectiveness of antiretroviral (ARV) therapy (ART), creating a growing population in whom age-related changes may influence treatment outcomes. Although aging is known to affect drug disposition, the molecular mechanisms by which aging alters ARV pharmacology remain incompletely understood, particularly within tissue compartments, including the rectosigmoid region of the colon, that serve as sites of HIV transmission and persistence. To address this knowledge gap, we used proteomics by liquid chromatography-mass spectrometry (LC-MS) to evaluate the impact of age and HIV status on proteins and pathways relevant to ARV disposition in peripheral blood mononuclear cells (PBMC) and rectosigmoid colon tissue obtained from young (18-50) HIV-seronegative adults, older (65-80) HIV-seronegative adults, and older virally suppressed people living with HIV. We found that aging and HIV infection differentially influenced proteins predominantly within nucleos(t)ide reverse transcriptase inhibitor (NRTI) pathways, in rectosigmoid tissue and PBMC. HIV-associated effects to the proteome were more prominent in PBMC, whereas aging produced broader alterations in ARV disposition-related proteins in rectosigmoid tissue, including proteins involved in drug transport, intracellular drug activation, dephosphorylation, and nucleotide homeostasis. Several age-associated changes were further influenced by biologic sex, suggesting that aging may not affect ARV disposition uniformly across populations. To place these findings within a broader context, pathway analyses were performed that identified extensive tissue-specific remodeling associated with aging and HIV infection involving drug disposition, immune regulation, cellular metabolism, and disease-related pathways. Notably, aging was associated with alterations in pathways relevant to nucleotide metabolism and gastrointestinal tissue function, suggesting that processes beyond traditional drug transport and metabolism pathways may contribute to variability in ARV disposition with advancing age. Together, these findings identify aging as an important modifier of pathways that regulate ARV disposition within compartments relevant to HIV transmission and persistence. While the clinical consequences of our findings are unknown, these data provide a mechanistic foundation for future studies investigating whether age-associated changes influence the effectiveness of ART and HIV pre-exposure prophylaxis in older adults.

pharmacology and toxicology↗