Retrospective analysis of dog study data from food and color additive petitions.

As part of the US FDA CFSAN's efforts to explore alternatives to animal testing, we retrospectively analyzed a sample of food additive (FAP) and color additive petitions (CAP) submitted to the FDA for the utility of dog study data in safety assessment. FAPs and CAPs containing dog studies (161 petitions) were classified as decisive (38%), supportive (27%), supplemental (29%) or undermined (6%) based on the impact the dog study data had on the final safety decision. Petitions classified as decisive were further categorized based on if the dog study data were used to a) address a safety concern (35/61); b) calculate an acceptable daily intake (ADI) (11/61); c) withdraw a petition (4/61); d) the effect was unique to the dog (2/61); or e) unclear (9/61). Of 11 petitions where the dog study was used to set an ADI, 7 contained studies where the points of departure (POD) from the dog studies were within an 8-fold range of the rodent with differences in study design likely contributing to the difference in PODs. Future research should include the development and use of qualified alternative studies to replace the use of animal testing for food and color additive safety assessment while ensuring human safety.

Update on Clinical Characteristics of Upper Airway Dyspnea: A Mixed Methods Study.

OBJECTIVES: Provide a mixed-methods update on clinical presentation of patients with upper airway dyspnea (UAD). STUDY DESIGN: Prospective, multicenter, mixed-methods study. METHODS: Data were collected from 30 patients presenting to two tertiary ENT clinics with a chief complaint of dyspnea. Exclusionary criteria included abnormal structural laryngeal findings, uncontrolled pulmonary disorders, and medical conditions affecting breathing. Objective data collected included laryngeal exam findings, patient-reported outcome measures and symptom questionnaires, medications, and psychological diagnoses. Patients were categorized into groups based on the chronic or episodic nature of their dyspnea symptoms for comparison. Qualitative data from these groups were collected and analyzed. RESULTS: Laryngeal exams revealed the presence of supraglottic constriction at rest was 26.66% and with phonation 83.33%. Ninety-three percent of patients did not show inappropriate vocal fold motion or adduction. Significant correlations were found between Dyspnea Index (DI) scores and other subjective questionnaires including Voice Handicap Index-10 (r = 0.64, P value = 0.001), Eating Assessment Tool-10 (r = 0.50, P value = 0.004), Cough Severity Index (r = 0.47, P value = 0.008), Vocal Cord Dysfunction Questionnaire (r = 0.59, P value = 0.005), and Somatic Symptom Scale-8 (r = 0.41, P value = 0.021). However, no significant correlation was found between the State-Trait Anxiety Index and DI (r = 0.27, P value = 0.1353). Qualitative analyses identified similar, but non-identical themes for both chronic and episodic dyspnea. CONCLUSIONS: Patients with symptoms of UAD also report other abnormal head and neck and global body symptoms. Most patients with complaints of UAD in this study did not have abnormal vocal fold movements on laryngoscopy. There were differences in qualitative analyses between the chronic and episodic dyspnea groups, but no differences in state or trait anxiety.

Food ingredient safety evaluation: Utility and relevance of toxicokinetic methods.

The use of toxicokinetic (TK) data is becoming more prevalent in the evaluation of food ingredient safety as more TK information is being incorporated in safety data packages. Data demonstrating "1) the extent of absorption, 2) tissue distribution, 3) pathways and rates of metabolism, and 4) rate(s) of elimination" of food ingredients and their metabolites of intermediate and high toxicological potential may be useful for planning and designing toxicity studies, selecting doses for toxicity studies, addressing species differences, and understanding the potential modes of action to evaluate their safety. TK data reported in the literature or generated from mechanistic TK studies can be analyzed using mathematical methods, including compartment and noncompartment TK methods, whose predictions can enhance interpretation of observed effects. Because of recent advancements, several approaches have been developed to improve sensitivity of analyses of available TK data and reduce uncertainty for evaluating safety of food ingredients. An example of advanced TK methods is physiologically-based TK (PBTK) modeling that incorporates physiological/biochemical parameters into a TK framework to predict internal exposure. In this review, we discuss the utility of some TK methods and explore their relevance and potential value for food ingredient safety evaluation. We also describe the strengths and limitations of these TK methods and discuss current challenges and opportunities for expanding their application for evaluating safety of food ingredients. This review represents a state of science report, and not a guidance document, on the utility and relevance of TK methods for the safety evaluation of food ingredients.