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 lowdose 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.Key words: TCDD; AHR; human B cells; dose response; risk assessment; genetic variability.Understanding of the dose-response relationship (DRR) for any given chemical lies at the heart of risk assessment. Traditionally, data derived from lab-based toxicology studies are extrapolated in assessing the potential adverse health effects of chemicals in the human population. As traditional laboratory-based toxicology studies are performed on a small number of individuals or inbred mouse strains and as chemical exposures occur in a heterogeneous population of individuals, there lies a disconnect between lab-based toxicology and population-level risk assessment. Little is known regarding the degree of variability in a DRR within a heterogeneous population (Rhomberg, 2011).A recent report published by the National Research Council (NRC) suggested that interindividual variability within the human population would effectively linearize the low-dose region of DRRs for all noncancer-causing chemicals (NRC, 2009).

Bridging the Data Gap From in vitro Toxicity Testing to Chemical Safety Assessment Through Computational Modeling

“…For instance, umbilical cord blood-derived cells were exploited to examine individual variability in the proliferative response to low-dose radiations ( 133 , 134 ). Primary human B lymphocytes from different donors were utilized to characterize the inter-individual variability in the immunotoxic effect of dioxin on the antibody secretion response and to ascertain how the variability may affect the linearization of the population-average dose response curves ( 21 ). Many of the studies with primary human cells use blood cells for their easy access; lack of easy access to solid living human tissues limits the usage of primary cells for toxicity testing.…”

“…Clearly some of the data gaps resulting from these challenges can be partially addressed or overcome through experimental and technological improvement, such as developing organ-on-a-chip and system-on-a-chip technology to better simulate chemical metabolism and physiological interactions, and using cells from a large number of donors to better represent human populations ( 19 – 21 ). However, there are fundamental limitations of the in vitro testing framework that cannot be easily improved through experimental means, and would require a computational approach to help bridge the data gaps in a feasible and cost-effective way ( 22 ).…”

Toxicodynamics of Mycotoxins in the Framework of Food Risk Assessment—An In Silico Perspective

“…In this framework, it has been developed the principle of personalized risk assessment that is referred to as the process where an individual’s level of risk is calculated using multiple predictors that are specific for an individual [ 88 ]. Such an approach is getting more and more attention as similar doses of specific xenobiotics may cause different responses not only among different species, but also among different individuals of the same species (e.g., [ 89 ]). Additionally, the presence of pathologic conditions may cause a more pronounced susceptibility making the personalized intervention even more needed for certain sub-population groups.…”

Characterizing Serpinb2 as a Modulator of TCDD-Induced Suppression of the B Cell

“…[13][14][15][16] In a previous study, B cells were isolated from 51 unique human donors, activated with CD40 ligand, and dosed with increasing concentrations of TCDD. 16 In comparing results across donors, profound interindividual variability was identified among the response to TCDD with up to 71-fold differences at the highest dose of TCDD (30 nM). While interindividual variability in response to toxicants can be driven by many factors, previous reports have shown that genetic background can have profound impacts on responses.…”