2015 Society of Toxicology Annual Meeting
San Diego, California, USA
March 22, 2015 – March 26, 2015
Mode of Action of the Effect of Trans Fatty Acids (TFAs) on LDL-Cholesterol and Implication for Dose Response
23 March 2015
Abstract Number: 224
Poster Board Number: 333
Abstract: The Food and Drug Administration (FDA) published a Federal Register notice tentatively determining that partially hydrogenated oils (PHOs, the primary dietary source of industrial TFAs– iTFAs) are no longer generally recognized as safe (GRAS) when used in food. This determination was based on the conclusion that there is no threshold intake for iTFA that would not increase an individual’s risk of coronary heart disease, based primarily on research showing iTFAs increase LDL-cholesterol (LDL-C) at high levels of intake. LDL-C is one of three surrogate endpoints for coronary heart disease risk recognized by the FDA. A Mode of Action (MOA) analysis was conducted for the relationship between iTFA dose and LDL-cholesterol. The MOA evaluation identified two key events: (1) increased VLDL levels, and (2) decreased LDL receptor activity. However, unlike classical MOAs, these two key events occur in parallel, rather than sequentially, presumably because fatty acids are nutrients regardless of configuration. The data were evaluated using the ILSI/IPCS MOA framework, based on the modified Hill criteria. The data for evaluating the temporal and dose responses for key events relative to the change in LDL-cholesterol were very limited, lacking sampling at early time points for key events. The result of this analysis and a holistic evaluation of the data indicates that the data overall are consistent with a nonlinear dose response and this is supported by physiology. LDL-cholesterol levels vary widely within an individual between fed and fasted states, indicating that there is a wide variability within the normal range. In addition, there is a large degree of regulation and feedback controls on every aspect of TFA transport, utilization and clearance, reflecting significant investment in maintenance of homeostatic levels. This analysis illustrates the utility of bringing a risk assessment perspective to the understanding of nutritional issues.
Presenting Author: Lynne Haber
This work was sponsored by the ILSI North America PHO Task Force.
Chemical Mixtures: Application of a Tiered Approach
24 March 2015
Abstract Number: 1377
Poster Board Number: 310
Abstract: Evaluating potential health risks posed by exposures to chemical mixtures is challenging for toxicology research and risk assessment. Considering the current challenges in food mixtures, a hypothetical case study was conducted using a tiered screening approach, that utilized simple conservative screening assumptions in lower tiers to focus resources on assessing chemicals of greater concern in higher tiers. Noncancer hazards associated with chronic oral exposures were evaluated using the hazard index (HI) method and the target organ toxicity dose approach (TTD). A hypothetical new bean product is being considered to replace pinto beans in a food program. Comparing old and new beans (NB) there is a 10% decrease in the following: cadmium (Cd), deltamethrin (De) and cyfluthrin. The What We Eat in America Food Commodity Intake Database (WWEIAFCID) was used to estimate pinto bean consumption rates (PBCR) in the general U.S. population in Tier 1. This tier provided a crude filter using recent, conservative health reference values for the mixture components. As the HI exceeded 1, in Tier 2, we refined PBCR distributions across different age groups and assessed exposures among Mexican Americans and children <12 years of age, groups exhibiting the highest PBCRs. HI estimates and the Risk 21 model were used to prioritize refinements in Tier 3; Cd and De were the largest contributors to HI in Tier 2. In Tier 3, De and Cd exposure estimates were refined using biomonitoring data and recent Cd intake estimates from Total Diet Study (2014), respectively. Between Tiers 2 and 3 the HI estimate decreased from 35 to 0.08 in the 95th percentile youth NB consumers. In Tier 4, constituents were grouped based on specific health effects, resulting in a HI estimate of 0.01 for NB among 95th percentile youth consumers using the TTD approach. Tiered approaches are useful and resource conserving as they can be implemented to effectively screen the effects of chemical mixtures in a health protective manner. This abstract does not necessarily reflect U.S. EPA policy.
Presenting Author: Mansi Krishan
This work on chemical mixtures was sponsored by the ILSI North America Technical Committee on Food & Chemical Safety
An Approach to Standardize the Concepts of “Lose Dose” and Nonmonotonic Dose Response in Toxicological Research and Regulatory Science
25 March 2015
Abstract Number: 1885
Poster Board Number: 434
Abstract: In order to facilitate impartial interpretation of research / discussions concerning the emerging concerns of non-monotonic ‘low-dose’ response; the need to establish mutual understanding of its fundamental terminology is essential. Although ‘non-monotonic’ ‘low-dose’ responses are most commonly interpreted as non-linear response at doses below previously tested levels, currently the literature is littered with variants of these terms in a variety of contexts each with varying degrees of precision and accuracy that confound debate of more important issues relevant to the ‘low-dose hypothesis.’ In the wake of emerging concerns of non-linear ‘low-dose’ response beyond endocrinology, such as nutrition (e.g. vitaminosis) and nanotechnology (Munger, Hadlock et al. 2014) this work sought to assess key literature and 1.) Identify the vast variation of interpretation of core concepts such as ‘low-dose, ‘response,’ and non-monotonic dose response, often limited to qualitative, circumstantial and subjective criteria; 2.) Present unbiased approaches to standardize interpretation of these terms based on a quantitative framework; 3.) Identify critical flaws that are prevalent amongst the body of literature that comprises the ‘low-dose hypothesis’; and 4.) Offer suggestions for future consideration. In doing so we have found, drastic inconsistencies in core concepts of the ‘low-dose hypothesis’ and offered a suggestive framework by which stakeholders can consider moving forward. In addition we have highlighted pervasive experimental inadequacies in key aspects of study design, statistics and inconsistent experimental replication, all of which collectively undermine the proposed findings and conclusions from exploratory ‘low-dose’ studies. Ultimately we culminate our work with suggestions to help further facilitate toxicological consideration of future ‘low dose’ studies.
Presenting Author: Joshua Vaughan
This work was sponsored by the ILSI North America Technical Committee on Food & Chemical Safety
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