Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action.

The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities. Implications for quantitative risk assessment approaches were discussed, as were implications of not considering MOA and dose in hazard characterization and labeling schemes. Most, but not all, participants considered the CAR and PPARα MOAs as not relevant to humans based on quantitative and qualitative differences. In contrast, cytotoxicity is clearly relevant to humans, but a threshold applies. Questions remain for all three MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs.

The use of PBPK models to inform human health risk assessment: case study on perchlorate and radioiodide human lifestage models.

Physiologically-based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well-defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium-iodide symporter (NIS). In this analysis, a six-step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer-reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near-term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.

Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: a pilot study.

BACKGROUND: Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction. PROCEDURE: A single institution open-label pilot study was conducted in childhood BT survivors: ≥1 year from cancer treatment; and who received >23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug. RESULTS: From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9-11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (P < 0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (P = 0.007), and the Number/Letter task (P = 0.018). CONCLUSIONS: Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.

The peabody picture vocabulary test as a pre-screening tool for global cognitive functioning in childhood brain tumor survivors.

Minimal acceptable global intelligence is often a determinant for entry into studies utilizing children's self-reported health-related quality of life (HRQL) or symptoms' appraisal. However, most measures of cognitive functioning are lengthy and require a trained psychologist for administration. We used the Peabody Picture Vocabulary Test (third edition; PPVT-III) to assess adequacy of verbal comprehension and language flexibility before entry into a pilot pharmacologic intervention trial in pediatric BT survivors who were >1 year from treatment, and received >23.4 gray as part of therapy. Participation included the ability to complete self-reported measures of HRQL. Among thirteen BT survivors who were screened, twelve proceeded to the full intervention trial and then underwent a detailed baseline neurocognitive assessment including the Wechsler Abbreviated Scale of Intelligence (WASI), administered by a neuropsychologist. Correlation of PPVT-III with WASI was 0.90 for full scale IQ (P < 0.0001), 0.89 for verbal IQ (P = 0.0001) and 0.75 for performance IQ (P = 0.0004) The PPVT-III is easy to administer by trained clinical staff and is a reliable clinic-based screening tool for research studies. While it is not designed to replace in depth neuropsychological evaluation of potential areas of cognitive dysfunction, it provides an estimation of minimal global cognitive functioning for entry into studies that rely on self-report in childhood BT survivors and other cancer survivors who have received central nervous system-directed therapy.

Assessing susceptibility from early-life exposure to carcinogens.

Cancer risk assessment methods currently assume that children and adults are equally susceptible to exposure to chemicals. We reviewed available scientific literature to determine whether this was scientifically supported. We identified more than 50 chemicals causing cancer after perinatal exposure. Human data are extremely limited, with radiation exposures showing increased early susceptibility at some tumor sites. Twenty-seven rodent studies for 18 chemicals had sufficient data after postnatal and adult exposures to quantitatively estimate potential increased susceptibility from early-life exposure, calculated as the ratio of juvenile to adult cancer potencies for three study types: acute dosing, repeated dosing, and lifetime dosing. Twelve of the chemicals act through a mutagenic mode of action. For these, the geometric mean ratio was 11 for lifetime exposures and 8.7 for repeat exposures, with a ratio of 10 for these studies combined. The geometric mean ratio for acute studies is 1.5, which was influenced by tissue-specific results [geometric mean ratios for kidney, leukemia, liver, lymph, mammary, nerve, reticular tissue, thymic lymphoma, and uterus/vagina > 1 (range, 1.6-8.1); forestomach, harderian gland, ovaries, and thyroid < 1 (range, 0.033-0.45)]. Chemicals causing cancer through other modes of action indicate some increased susceptibility from postnatal exposure (geometric mean ratio is 3.4 for lifetime exposure, 2.2 for repeat exposure). Early exposures to compounds with endocrine activity sometimes produce different tumors after exposures at different ages. These analyses suggest increased susceptibility to cancer from early-life exposure, particularly for chemicals acting through a mutagenic mode of action.

Bioterrorism preparedness. II: The community and emergency medical services systems.

Disaster planning is an arduous task. Perhaps no form of disaster is more difficult to prepare for than one resulting from the intentional, covert release of a biological pathogen or toxin. The complexities of response operations and the perils of inadequate preparation cannot be overemphasized. Even with detailed planning, deviations from anticipated emergency operations plans are likely to occur. Several federal programs have been initiated to assist communities in enhancing their preparedness for events involving biological and other agents of mass destruction. Many of these, such as the Metropolitan Medical Response Systems (MMRS) Program [37,38], will be discussed elsewhere. Community preparedness will be enhanced by: 1. Implementing a real-time public health disease surveillance program linking local healthcare, emergency care, EMS, the CDC, local law enforcement, and the FBI 2. Improved real-time regional patient and healthcare capacity status management 3. Development of affordable, accurate biological agent detection systems 4. Incorporation of standardized education and training curricula (appropriate for audience) on terrorism and biological agents into healthcare training programs 5. Expansion of federal and state programs to assist communities in system development 6. Increased public awareness and education programs.

Incorporating new technologies into toxicity testing and risk assessment: moving from 21st century vision to a data-driven framework.

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency.

Biological parametric mapping: A statistical toolbox for multimodality brain image analysis.

In recent years, multiple brain MR imaging modalities have emerged; however, analysis methodologies have mainly remained modality-specific. In addition, when comparing across imaging modalities, most researchers have been forced to rely on simple region-of-interest type analyses, which do not allow the voxel-by-voxel comparisons necessary to answer more sophisticated neuroscience questions. To overcome these limitations, we developed a toolbox for multimodal image analysis called biological parametric mapping (BPM), based on a voxel-wise use of the general linear model. The BPM toolbox incorporates information obtained from other modalities as regressors in a voxel-wise analysis, thereby permitting investigation of more sophisticated hypotheses. The BPM toolbox has been developed in Matlab with a user-friendly interface for performing analyses, including voxel-wise multimodal correlation, ANCOVA, and multiple regression. It has a high degree of integration with the SPM (statistical parametric mapping) software relying on it for visualization and statistical inference. Furthermore, statistical inference for a correlation field, rather than a widely used T-field, has been implemented in the correlation analysis for more accurate results. An example with in vivo data is presented, demonstrating the potential of the BPM methodology as a tool for multimodal image analysis.