title: The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells.
abstract: The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the low-dose region. To address this knowledge gap and directly test the NRC's assumption, this study focused on assessing the DRR between 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) exposure and immune suppression in a cohort of unique human donors. Human B cells were isolated from 51 individual donors and treated with logarithmically increasing concentrations of TCDD (0-30 nM TCDD). Two endpoints sensitive to TCDD were assessed: (1) number of IgM-secreting B cells and (2) quantity of IgM secreted. The results show that TCDD significantly suppressed both the number of IgM-secreting B cells and the quantity of IgM secreted (P < .05). Statistical model comparisons indicate that the low-dose region of the two DRRs is best explained with a nonlinear relationship. Rather than assuming low-dose linearity for all noncancer-causing DRRs, our study suggests the need to consider the specific mode of action of toxicants and pharmaceuticals during risk-management decision making.
authors.affiliation: *Department of Biochemistry and Molecular Biology Institute for Integrative Toxicology.
authors.forename: Peter
authors.initials: P
authors.lastname: Dornbos
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.affiliation: Department of Pharmacology and Toxicology Institute for Integrative Toxicology.
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
authors.affiliation: Center for Statistical Training & Consulting.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hession
authors.affiliation: *Department of Biochemistry and Molecular Biology Institute for Integrative Toxicology Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, Michigan lapres@cns.msu.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: LaPres
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology; D018920:Coculture Techniques; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D008213:Lymphocyte Activation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
chemical_list: D007075:Immunoglobulin M; D000072317:Polychlorinated Dibenzodioxins; D023201:CD40 Ligand
keywords: AHR; TCDD; dose response; genetic variability; human B cells; risk assessment