Linear‐No‐Threshold Default Assumptions for Noncancer and Nongenotoxic Cancer Risks: A Mathematical and Biological Critique

Bogen, Kenneth T.

doi:10.1111/risa.12460

Cited by 23 publications

(33 citation statements)

References 34 publications

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“…The NRC did not evaluate the potential effect of population heterogeneity with adequate peer-reviewed data sets (NRC, 2009). Foremost, the NRC's assumption generalizes the shape of the low-dose region for all chemical exposures; however, as chemicals have different modes of action, it is unlikely that all chemically affected biological processes, such as receptor-mediated events, will result in a linear low-dose region (Bogen, 2016). Given the potential risks associated with invalid assumptions in regards to the low-dose regions of noncancer DRRs, such as unsafe exposures in susceptible individuals and financial burden associated with the chemical monitoring and cleanup, the NRC's assumption warrants further scrutiny and evaluation.…”

Section: Discussionmentioning

confidence: 99%

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

Dornbos¹,

Crawford²,

Kaminski³

et al. 2016

Toxicol. Sci.

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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).

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Section: Discussionmentioning

confidence: 99%

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

Dornbos¹,

Crawford²,

Kaminski³

et al. 2016

Toxicol. Sci.

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“…In its "Silver Book," (2) the National Research Council (NRC) Science and Decisions Committee proposed methods for unifying risk assessment procedures that would involve developing quantitative estimates of risk for all health effects. The paradigm for risk assessment proposed by the Committee is based on three conceptual models 1 Throughout this article the NRC (2) terminology is used so that by a "linear" dose response is meant one with "low-dose linearity" defined as a dose response having a positive slope (positive derivative) at zero dose, and by "nonlinear" is meant a doseresponse that does not have this feature. The term "linear-nothreshold" (LNT), in keeping with standard practice, will also refer to a dose response that is low-dose linear, rather than being restricted to only dose responses that are perfectly linear over some finite dose range.…”

Section: Introductionmentioning

confidence: 99%

“…An article published earlier in this journal (Bogen (1) ) was critical of the arguments for linear dose responses underlying Conceptual Models 1 and 3, claiming that the SIH argument for linearity is false and the AB argument is "either false or effectively meaningless." In this article I evaluate Bogen's critique.…”

Section: Introductionmentioning

confidence: 99%

“…

In an article recently published in this journal, Bogen (1) concluded that an NRC committee's recommendations that default linear, nonthreshold (LNT) assumptions be applied to doseresponse assessment for noncarcinogens and nonlinear mode of action carcinogens are not justified. Bogen criticized two arguments used by the committee for LNT: when any new dose adds to a background dose that explains background levels of risk (additivity to background or AB), or when there is substantial interindividual heterogeneity in susceptibility (SIH) in the exposed human population.

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confidence: 99%

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Bogen's Critique of Linear‐No‐Threshold Default Assumptions

Crump¹

2016

Risk Analysis

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In an article recently published in this journal, Bogen concluded that an NRC committee's recommendations that default linear, nonthreshold (LNT) assumptions be applied to dose- response assessment for noncarcinogens and nonlinear mode of action carcinogens are not justified. Bogen criticized two arguments used by the committee for LNT: when any new dose adds to a background dose that explains background levels of risk (additivity to background or AB), or when there is substantial interindividual heterogeneity in susceptibility (SIH) in the exposed human population. Bogen showed by examples that SIH can be false. Herein is outlined a general proof that confirms Bogen's claim. However, it is also noted that SIH leads to a nonthreshold population distribution even if individual distributions all have thresholds, and that small changes to SIH assumptions can result in LNT. Bogen criticizes AB because it only applies when there is additivity to background, but offers no help in deciding when or how often AB holds. Bogen does not contradict the fact that AB can lead to LNT but notes that, even if low-dose linearity results, the response at higher doses may not be useful in predicting the amount of low-dose linearity. Although this is theoretically true, it seems reasonable to assume that generally there is some quantitative relationship between the low-dose slope and the slope suggested at higher doses. Several incorrect or misleading statements by Bogen are noted.

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“…The soundness of this recommendation has been questioned (Rhomberg et al, 2011;Bogen, 2016). (Rhomberg et al, 2011).…”

Section: Challenge 2: When To Use Ttc?mentioning

confidence: 99%

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

Hartung

2017

ALTEX

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Linear‐No‐Threshold Default Assumptions for Noncancer and Nongenotoxic Cancer Risks: A Mathematical and Biological Critique

Cited by 23 publications

References 34 publications

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

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

Bogen's Critique of Linear‐No‐Threshold Default Assumptions

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

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