43rd Winter Meeting Program Overview
The scientific program of The Toxicology Forum’s 43rd Annual Winter Meeting features a series of diverse scientific sessions that bring together differing scientific viewpoints from leading government regulators, industry scientists, and academic researchers for dynamic presentations and discussions on emerging topics in toxicology. The format of meeting sessions at The Forum allows for deliberative dialogue which shapes decision-making and outcomes on critical issues in toxicology and its applications in a small, collegial setting, that differs from other meetings.
Safety Assessment of Genetically Engineered Food Crops: Screening Methods, Safety Concerns, and Current US Regulation ▸
Foods derived from genetically engineered (GE) crops are increasingly available to consumers, while the potential health hazard of such foods continues to be debated. The necessity of specific testing for GE crops vs. traditional crops is also controversial, and is not standardized. This session will address some of the specific safety concerns and challenges faced by industry scientists and regulators, as well as a history of safe use of some GE crops.
Non-Genotoxic Impurities in Pharmaceuticals—Is it Time to Review Acceptance Levels, Specifications and Toxicology Qualification?▸
Management of non-mutagenic impurity levels in pharmaceutical drug substance and drug product is guided by ICH Q3A and Q3B. If the level of an impurity(s) is higher than the acceptance level in these guidances and was present in appropriate GLP toxicology studies, it is considered qualified for clinical use. If new impurities, or higher levels of a previously present impurity are present in subsequent manufacturing batches, qualification in additional animal studies is required prior to release for clinical use. Initially published in 2006, the application and scientific understanding around impurity qualification has continued to evolve. This has led to challenges for process chemistry as the expectations for impurity control can change or be inconsistently applied. One example of this evolution is for early phase clinical trials. There is a regulatory expectation that pharmaceutical sponsors ensure impurity control and qualification of impurities in these early trials. While early phase clinical trials are outside the scope of ICH Q3A / B, no other guidelines exist for control of ordinary impurities at this stage. Qualification thresholds listed in ICH Q3A and Q3B are too restrictive at this stage of development since the process chemistry is still being developed and limited batches are available. A recent publication by Harvey et al, (2017) following from an EFPIA workshop in 2012, put forward a scientific approach for using a modified Haber’s law approach (similar to what was used for ICH M7) to support the acceptance of higher qualification thresholds for impurities and degradation products in early clinical trials of durations less than 6 months. Other harmonization efforts are needed to facilitate consistent and safe manufacturing of active pharmaceuticals while instituting the 3Rs principles for animal testing such as study harmonization for impurity toxicity qualification studies, using human data to qualify impurities, qualification thresholds for anticancer compounds that fall under ICH S9 or short-term indications and calculating new qualified levels of impurities based on animal toxicity data. It is hoped that the discussion will facilitate consistency in the application of ICH Q3A and Q3B.
Mixtures Toxicology: Moving from Addition to Prediction▸
Research in mixtures toxicology has sought relevance to risk assessment by focusing on whether chemicals in mixtures conform to classic models of additive combined action: Independent Action (IA), Concentration Addition (CA), or hybrid models of CA and IA. This focus may have inadvertently stifled progress in mixtures toxicology research by narrowing the range of questions addressed and by ignoring limitations that prevent either model from accurately predicting or explaining certain realities regarding the toxicological behavior of mixtures. For example, IA does not predict or explain why some chemicals with apparently dissimilar modes of action (MoAs) may produce effects even when present in a mixture at doses below their NOAELs. Conversely, CA does not predict or explain why organisms thrive amidst complex mixtures of tens of thousands of chemicals, many of which can affect biological processes by similar MoAs when at concentrations higher than those present physiologically or in the ambient environment. These limitations arise because of problems related to both mathematical and biological extrapolation. Even when IA and CA give distinctly different predictions within the dose ranges tested experimentally, biological variability alone can render such predictions indistinct when extrapolated to untested dose ranges; the resulting uncertainties cannot be reduced by repetition within the experimentally tested range. Second, the mechanistic basis of combined action can be dose-dependent, thus restricting the domain of applicability of either CA or IA to the dose ranges tested. Recent research suggests that these limitations can be overcome by augmenting the use of IA and CA with mechanistic research and computational modeling that seeks to understand how dose-dependent transitions in mechanisms of action affect the toxicological behavior of chemical mixtures and how mixtures affect control nodes in biological networks. Computational modeling can be used to organize and conceptualize mechanistic data from mixtures in which the combined action of components is understood to pose testable hypotheses regarding the toxicological behavior of unknowns. This session will explain how, taken together, these research approaches can help to advance the field of mixtures toxicology and expand its predictive capability for risk and safety assessment.
Deciphering Different Approaches to Benchmark Dose Methodologies▸
The US EPA and EFSA have provided guidance for the use of BMD analysis and while quite similar there are a few specific issues on which they diverge. As such, different risk assessors may derive different values for the BMD using the same data. Thus, it is of interest to know the basic differences in each approach, the underlying principles, and the nature and extent of the impact on the BMD.
The presentation will outline the arguments behind the various viewpoints with respect to the biological and statistical approaches and promote consensus on each of the issues.
The Re-Emergence of Cannabis: New Frontiers in the Potentials and Pitfalls of Inhalation and Oral Exposures▸
The transition from drug to recreational exposure to edible cannabis products represents a significant public health issue in the virtual absence of classic safety and transitional toxicology assessments. The exponential increase in emergency department events related to cannabis usage illustrates the critical need for harmonization of regulations, standardization of production, establishment of validated analytical procedures, as well as increased understanding of clinical and public health consequences and consistency in policy agendas.
Hazard Identification: Is Hazard Classification Valid without Context of Exposure? ▸
Hazard evaluations have traditionally been conducted to identify the “inherent properties” of an agent to cause adverse effects. The identification of these hazards is often considered to be a critical step in the risk assessment of an agent when integrated with an exposure assessment. However, studies conducted to evaluate hazards (both in vivo and in vitro) are conducted at (very) high doses, and in many cases the hazard identified is driven by a high dose mechanism that would not occur at levels far above the relevant environmental human exposure. When these high dose hazards are identified and presented independent of a risk assessment, the labeling associated with the agent can have significant consequences, ranging from unwarranted public concern and/or confusion to a complete ban of the chemical from certain uses (e.g., cosmetics). This session will provide an overview of hazard identification as it relates to classification and labeling, case studies for cancer and endocrine disruption, and implications for the acceptance of emerging technologies.