Safety Assessment Of Products Research Articles

A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products.

Through two decades of research and development, adoptive cell therapies (ACTs) have revolutionized treatment for hematologic malignancies. Many of the seven US Food and Drug Administration (FDA)-approved products are proven to be a curative last line of defense against said malignancies. The ACTs, known more commonly as chimeric antigen receptor (CAR) T-cells, utilize engineered lymphocytes to target and destroy cancer cells in a patient-specific, major histocompatibility complex (MHC)-independent manner, acting as "living drugs" that adapt to and surveil the body post-treatment. Despite their efficacy, CAR T-cell therapies present unique challenges in preclinical safety assessment. The safety and pharmacokinetics of CAR T-cells are influenced by numerous factors including donor and recipient characteristics, product design, and manufacturing processes that are not well-predicted by existing in vitro and in vivo preclinical safety models. The CAR therapy-mediated toxicities in clinical settings primarily arise from unintended targeting of non-tumor cells, potential tumorigenicity, and severe immune activation syndromes like cytokine release syndrome and immune effector cell-associated neurotoxicity. Addressing these issues necessitates a deep understanding of CAR target expression in normal tissues, inclusive of the spatial microanatomical distribution, off-target screening, and a deep understanding CAR cell manufacturing practices and immunopathology.

Bayesian network analysis of risk classification strategies in the regulation of cellular products

Cell therapy, a burgeoning therapeutic strategy, necessitates a scientific regulatory framework but faces challenges in risk-based regulation due to the lack of a global consensus on risk classification. This study applies Bayesian network analysis to compare and evaluate the risk classification strategies for cellular products proposed by the Food and Drug Administration (FDA), Ministry of Health, Labour and Welfare (MHLW), and World Health Organization (WHO), using real-world data to validate the models. The appropriateness of key risk factors is assessed within the three regulatory frameworks, along with their implications for clinical safety. The results indicate several directions for refining risk classification approaches. Additionally, a substudy focuses on a specific type of cell and gene therapy (CGT), chimeric antigen receptor (CAR) T cell therapy. It underscores the importance of considering CAR targets, tumor types, and costimulatory domains when assessing the safety risks of CAR T cell products. Overall, there is currently a lack of a regulatory framework based on real-world data for cellular products and a lack of risk-based classification review methods. This study aims to improve the regulatory system for cellular products, emphasizing risk-based classification. Furthermore, the study advocates for leveraging machine learning in regulatory science to enhance the assessment of cellular product safety, illustrating the role of Bayesian networks in aiding regulatory decision-making for the risk classification of cellular products.

Safety assessment of agricultural products and the pesticide regulation trend in China

The sustainable development of Chinese agriculture needs to coordinate the quality and quantity of agricultural products. To verify whether government regulation can promote agricultural development by controlling pesticides, the indices of government regulation, quantity and quality of agricultural products, and pesticide use per area of cropland were calculated, and a comprehensive evaluation index and the coupling degree and coordination degree of agricultural products were analyzed by coupling function. The results showed that the coupling and coordination degree of the quality and quantity of agricultural products and the comprehensive index are improving. The regulation of pesticide use per area of cropland is a key mechanism in promoting the coordinated development of agricultural product safety. The regulation trend of agricultural development in China is to reduce pesticide usage appropriately and expand the production-possibility frontier of agricultural products.Graphical abstract

A standardized chamuangone enriched extract from Garcinia cowa Roxb. leaves shows acute and sub-acute safety

Ethnopharmacological relevanceThe safety assessment of herbal products is critical for their appropriate pharmacological applications. Garcinia cowa Roxb., commonly known as Cha-muang in Thai, has ethnopharmacological relevance for inflammation, infectious diseases, and diabetes. The leaf extracts of G. cowa have been extensively reported for their anticancer, anti-inflammatory, antimicrobial, and antioxidant effects. Notably, chamuangone is their major active constituent that contributes to various pharmacological properties. Aim of the studyThe current study aims to establish a standardized chamuangone enriched extract (CEE) and assess its acute and sub-acute toxicities in animal models. MethodologyCEE was established from G. cowa leaves using a microwave-assisted extraction (MAE), followed by fractionation and enrichment through silica gel vacuum and column chromatography. The concentration of chamuangone in the extract was quantified using a validated quantitative high-performance liquid chromatography (HPLC) method. The safety profiles of CEE were thoroughly evaluated in rodents according to the Organization for Economic Cooperation and Development (OECD) 425 and 407 guidelines. The effects on oxidative stress markers such as superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and malondialdehyde (MDA) levels were also evaluated in various organs. ResultsBased on the quantitative HPLC analysis, the CEE contained 73.0 ± 2.0% w/w of chamuangone. In the acute toxicity study, following up and down procedure the female rats were dosed with CEE at 1750 and 550 mg/kg body weight (b.w.), with CEE 1750 mg/kg b.w. was toxic, causing mortality, while CEE 550 mg/kg b.w. was deemed safe. An LD50 value was calculated according to the standard protocols, resulting in 970 mg/kg b.w. In histopathological examination, 550 mg/kg b.w. of CEE was safe in all the selected organs, while the 1750 mg/kg b.w. CEE treated rats exhibited toxic effects in histological tissues sections in the form of necrosis in the brain, cardiac muscle hypertrophy, liver inflammation, mild untoward effect in the spleen, fibrosis in the lungs, pancreatitis, pyelonephritis, and ovarian cyst. Administration of CEE at doses of 550 mg/kg b.w. (single dose) in the acute and 100 mg/kg b.w. (regularly 28-days) in the sub-acute toxicity studies significantly (p < 0.05) decreased levels of uric acid, triglycerides, and cholesterol. Importantly, the CEE (550 and 100 mg/kg b.w.) also significantly increased the levels of antioxidant enzymes (SOD, GSH, and CAT) and decreased MDA levels. Normal histopathology was observed in the sub-acute toxicity study in all treated groups. ConclusionThis study successfully concludes that CEE at a dose of 100 mg/kg b.w. is safe for therapeutic application or use as a chemopreventive functional food utilizing green extraction methods. However, chronic toxicity studies are further recommended to validate safety concerns over an extended period.

Bioactivation of cinnamic alcohol in a reconstructed human epidermis model and evaluation of sensitizing potency of the identified metabolites.

Cinnamic alcohol is a natural compound, widely used in fragrances, which can cause allergic contact dermatitis. Cinnamic alcohol lacks intrinsic reactivity and autoxidation or metabolic activation is necessary for it to act as a sensitizer. Bioactivation of cinnamic alcohol was explored using human liver microsomes, human liver S9 and SkinEthic™ Reconstructed Human Epidermis. A targeted multiple reaction monitoring mass spectrometry method was employed to study and quantify cinnamic alcohol along with eight potential phase I or phase II metabolites. The reconstructed human epidermis model, treated with cinnamic alcohol, was also analyzed with a non-targeted high-resolution mass spectrometry method to identify metabolites not included in the targeted method. Two metabolites identified with the targeted method, namely, pOH-cinnamic alcohol and pOH-cinnamic aldehyde, have not previously been identified in a metabolic in vitro system. Their reactivity toward biologically relevant nucleophiles was investigated and compared to their sensitizing potency in vivo in the murine local lymph node assay (LLNA). According to the LLNA, the pOH-cinnamic alcohol is non-sensitizing and pOH-cinnamic aldehyde is a moderate sensitizer. This makes pOH-cinnamic aldehyde less sensitizing than cinnamic aldehyde, which has been found to be a strong sensitizer in the LLNA. This difference in sensitizing potency was supported by the reactivity experiments. Cinnamic sulfate, previously proposed as a potential reactive metabolite of cinnamic alcohol, was not detected in any of the incubations. In addition, experiments examining the reactivity of cinnamic sulfate toward a model peptide revealed no evidence of adduct formation. The only additional metabolite that could be identified with the non-targeted method was a dioxolan derivative. Whether or not this metabolite, or one of its precursors, could contribute to the sensitizing potency of cinnamic alcohol would need further investigation. Cinnamic alcohol is one of the most common fragrance allergens and as it is more effective to patch test with the actual sensitizer than with the prohapten itself, it is important to identify metabolites with sensitizing potency. Further, improved knowledge of metabolic transformations occurring in the skin can improve prediction models for safety assessment of skin products.

Safety assessment of polypropylene self-heating food container: The release of microplastics and volatile organic compounds

The safety assessment of food-contact plastic products is crucial for protecting consumers from potential harmful chemical contaminants. This study investigated novel contaminants and substances of concern in self-heating food containers, focusing on the release of microplastics (MPs) and the migration of volatile organic compounds (VOCs). Using micro-Raman spectroscopy, we simulated actual self-heating condition to determine the abundance, size, and size distribution of released MPs. Results showed MPs abundance ranging from 1.7 × 106 to 3.4 × 106 particles/L, with an average of 2.4 × 106 particles/L, where over 98 % of particles were smaller than 20 µm. For VOCs migration, we employed direct immersion solid-phase micro-extraction coupled with comprehensive two-dimensional gas chromatograph-tandem quadrupole-time-of-flight mass spectrometry (DI-SPME-GC×GC-QTOF-MS) under three migration conditions. We identified 41 VOCs, including saturated hydrocarbons, fatty acyls, organoxygen compounds, unsaturated hydrocarbons, benzene derivatives, and phenol ethers. Risk substances such as Dibutyl phthalate, Benzophenone, and 4-Methylbenzophenone were detected in three samples. Semi-quantitative analysis and toxicity classification revealed that the maximum migration of all analytes remained below corresponding limit values, indicating a generally low risk to consumers.

Multisite studies for optimization of a highly efficient culture assay used for in vitro detection of residual undifferentiated human pluripotent stem cells intermingled in cell therapy products

IntroductionMEASURE2 (Multisite Evaluation Study on Analytical Methods for Non-clinical Safety Assessment of HUman-derived REgenerative Medical Products 2) is a Japanese experimental public–private partnership initiative that aims to standardize testing methods for tumorigenicity evaluation of human pluripotent stem cell (hPSC)-derived cell therapy products (CTPs). MEASURE2 organized multisite studies to optimize the methodology of the highly efficient culture (HEC) assay, a sensitive culture-based in vitro assay for detecting residual undifferentiated hPSCs in CTPs. MethodsIn these multisite studies, 1) the efficiency of colony formation by human induced pluripotent stem cells (hiPSCs) under two different culture conditions and 2) the sorting efficiency of microbeads conjugated to various anti-hPSC markers during hiPSC enrichment were evaluated using samples in which hiPSCs were spiked into hiPSC-derived mesenchymal stem cells. ResultsThe efficiency of colony formation was significantly higher under culture conditions with the combination of Chroman 1, Emricasan, Polyamines, and Trans-ISRIB (CEPT) than with Y-27632, which is widely used for the survival of hPSCs. Between-laboratory variance was also smaller under the condition with CEPT than with Y-27632. The sorting efficiency of microbeads conjugated with the anti-Tra-1-60 antibody was sufficiently higher (>80%) than those of the other various microbeads investigated. ConclusionsResults of these multisite studies are expected to contribute to improvements in the sensitivity and robustness of the HEC assay, as well as to the future standardization of the tumorigenicity risk assessment of hPSC-derived CTPs.

Safety assessment of some food products with reference to adulteration in Faisalabad, Punjab, Pakistan

Safety assessment of some food products with reference to adulteration in Faisalabad, Punjab, Pakistan

Metagenomic profiles of the antimicrobial resistance in traditional Chinese fermented meat products: Core resistome and co-occurrence patterns

Antimicrobial resistance (AMR) poses a significant challenge to global health, and the presence of antibiotic resistance genes (ARGs) in food poses a potential threat to public health. Traditional Chinese fermented meat products (FMPs) are highly favored because of their unique flavors and cultural value. However, microbial safety and the potential distribution and composition of AMR in these products remain unclear. In this study, a comprehensive analysis of bacterial composition and antibiotic-resistant populations in 216 samples of traditional fermented meat products from different regions of China was conducted using a metagenomic approach. Staphylococcus was the most abundant genus in the samples, accounting for an average abundance of 29.9 %, followed by Tetragenococcus (17.1 %), and Latilactobacillus (3.6 %). A core resistome of FMP samples was constructed for the first time using co-occurrence network analysis, which revealed the distribution and interrelationships of ARGs and bio/metal-resistant genes (BMRGs). Random forest analysis identified the lincosamide nucleotidyltransferase lnuA and the multidrug and toxic compound extrusion (MATE) transporter abeM as potential indicators for assessing the overall abundance of the core resistome. Additionally, Staphylococcus, Acinetobacter, and Pseudomonas were identified as hosts constituting the core resistome. Despite their low abundance, the latter two still serve as major reservoirs of antibiotic resistance genes. Notably, Lactococcus cremoris was identified as the key host for tetracycline resistance genes in the samples, highlighting the need for enhanced resistance monitoring in lactic acid bacteria. Based on our findings, in the microbial safety assessment of fermented meat products, beyond common foodborne pathogens, attention should be focused on detecting and controlling coagulase-negative Staphylococcus, Acinetobacter, and Pseudomonas, and addressing bacterial resistance. The quantitative detection of lnuA and abeM could provide a convenient and rapid method for assessing the overall abundance of the core resistome. Our findings have important implications for the control of bacterial resistance and prevention of pathogenic bacteria in fermented meat products.

A roadmap towards a human-centric safety assessment of advanced therapy medicinal products

Advanced therapy medicinal products (ATMPs) are among the most complex pharmaceuticals with high human specificity. Species differences severely limit the clinical relevance of in vivo data. We conducted interviews with stakeholders involved in ATMP development about their perspective on the use of in vivo studies, the perceived hurdles and associated potential solutions regarding non-clinical development of ATMPs. In total, 17 stakeholders from 9 different countries were interviewed. A workshop was held with key stakeholders to further discuss major topics identified from the interviews. Conducting in vivo studies remains the status quo for ATMPs development. The hurdles identified included determining the amount of information required before clinical entry and effective use of limited human samples to understand a treatment or for clinical monitoring. A number of key points defined the need for future in vivo studies as well as improved application and implementation of New Approach Methodology (NAM)-based approach for products within a well-known modality or technology platform. These included data transparency, understanding of the added value of in vivo studies, and continuous advancement, evaluation, and qualification of NAMs. Based on the outcome of the discussions, a roadmap with practical steps towards a human-centric safety assessment of ATMPs was established.

Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values.

On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.

Recent advances on surface enhanced Raman spectroscopy in safety assessment and quality control of meat and meat products

Recent advances on surface enhanced Raman spectroscopy in safety assessment and quality control of meat and meat products

Laboratory Performance Study of the Japanese Official Method to Detect Genetically Modified Papaya Line PRSV-YK

Since the establishment of procedures for the safety assessment of food products that use recombinant DNA technology, the manufacture, import, and sale of genetically modified (GM) foods that have not undergone safety assessment are prohibited under the Food Sanitation Act. Therefore, a performance study to confirm the GM food testing operations of each laboratory is very important to ensure the reliability of the GM food monitoring system. In 2022, GM papaya line PRSV-YK-which has not yet been authorized in Japan-was selected for testing, and a papaya paste and a DNA solution were used as the test samples. With these samples, a laboratory performance study of the DNA extraction and real-time PCR operations was conducted. This confirmed that the 18 participating laboratories were generally performing the DNA extraction and real-time PCR operations correctly. However, some laboratories using certain DNA amplification reagent with some real-time PCR instruments were not able to determine the PRSV-YK detection test. This suggests that the PRSV-YK detection test may not be able to correctly detect samples containing GM papaya when performed with these combinations of instruments and reagent. In order to ensure the reliability of the PRSV-YK detection test, it is necessary to examine in detail how the combination of DNA polymerase reagents and real-time PCR instruments affects the detection limit, and to implement an appropriate solution.

A (not) new Rx: Quality Improvement for NAM

New Approach Methodologies (NAMs) are a rapidly growing set of tools/methods for use food, drug, consumer product, or chemical safety assessment paradigms. The massive growth in NAMs tech development, publication, and legislation has been paralleled by a growing sense of frustration. The challenge of realizing the systems-level changes needed to catalyze the broad-scale adoption and use of NAMs is substantial. This Commentary asserts that these challenges may be less unique than perceived to date, and points to specific opportunities to learn from decades of experience (both positive and negative) from the Quality Improvement (QI) movement in the public health and healthcare arenas. Specific recommendations to inform and guide NAMs development are offered.

Optimisation of Approaches to Adverse Event Analysis in Bioequivalence Clinical Trials

SCIENTIFIC RELEVANCE. The safety assessment of investigational medicinal products is a mandatory step in clinical trials of all phases, including bioequivalence studies. However, there are no approaches providing for the individualised assessment of adverse drug reactions (ADRs), which contributes to the quality of decisions on the safety of pharmacotherapy.AIM. The study aimed to develop and justify approaches to the individualised assessment of the safety of pharmacotherapy based on quantitative integrative analysis of adverse events (AEs).MATERIALS AND METHODS. The authors carried out a systematic review of open-access publications and adapted quantitative integrative analysis methods for assessing the safety of pharmacotherapy in clinical trials involving healthy volunteers. The developed methodology is a step-by-step individualised assessment of ADRs, where each case is assigned a certain score and a weight, with subsequent data aggregation to obtain an integrated indicator at the system/organ and organism levels.RESULTS. The authors developed a five-step procedure for assessing the safety of pharmacotherapy based on quantitative integrative ADR analysis. This procedure involves scoring an AE, converting the score using membership functions, assigning weights, aggregating data to obtain an integrated indicator, and interpreting individual and group indicators. The sequential implementation of the analysis steps in accordance with the proposed procedure makes it possible to assign each volunteer (study subject) to a specific group in accordance with the likelihood of developing AEs. In addition to individual assessment, the article presents an algorithm for interpreting indicators for groups of study subjects, depending on the treatment group (study or comparator medicinal product).CONCLUSIONS. The described algorithm for converting and presenting integrative AE assessments will improve the reliability and validity of conclusions on the safety of medicinal products, which is important for planning and implementing further clinical development programmes.

Brazilian National Network of Alternative Methods (RENAMA) 10th Anniversary: Meeting of the Associated Laboratories, May 2022.

The Brazilian National Network of Alternative Methods (RENAMA), which is linked to the Ministry of Science, Technology and Innovation, is currently comprised of 51 laboratories from CROs, academia, industry and government. RENAMA's aim is to develop and validate new approach methodologies (NAMs), as well as train researchers and disseminate information on their use - thus reducing Brazilian, and consequently Latin American, dependence on external technology. Moreover, it promotes the adoption of NAMs by educators and trained researchers, as well as the implementation of good laboratory practice (GLP) and the use of certified products. The RENAMA network started its activities in 2012, and was originally comprised of three central laboratories - the National Institute of Metrology, Quality and Technology (INMETRO); the National Institute of Quality Control in Health (INCQS); and the National Brazilian Biosciences Laboratory (LNBio) - and ten associated laboratories. In 2022, RENAMA celebrated its 10th anniversary, a milestone commemorated by the organisation of a meeting attended by different stakeholders, including the RENAMA-associated laboratories, academia, non-governmental organisations and industry. Ninety-six participants attended the meeting, held on 26 May 2022 in Balneário Camboriú, SC, Brazil, as part of the programme of the XXIII Brazilian Congress of Toxicology 2022. Significant moments of the RENAMA were remembered, and new goals and discussion themes were established. The lectures highlighted recent innovations in the toxicological sciences that have translated into the assessment of consumer product safety through the use of human-relevant NAMs instead of the use of existing animal-based approaches. The challenges and opportunities in accepting such practices for regulatory purposes were also presented and discussed.

Removal of ochratoxin A in wine by Cryptococcus albidus and safety assessment of degradation products.

Ochratoxin A (OTA) is a mycotoxin that contaminates grape-based products and is extremely harmful to the health of the host. It is effectively removed by yeast during the fermentation of wine, whereas the removal mechanism of OTA remains unclear. Therefore, the present study aimed to investigate the removal mechanism of ochratoxin A by yeast and to evaluate the safety of its degradation products. Cryptococcus albidus (20-G) with better effect on ochratoxin A (OTA) was screened out in the main fermentation stage of wine. The results showed that 20-G removed OTA through biosorption and biodegradation. Intracellular enzymes played the main role (18.44%) and yeast cell walls adsorbed a small amount of OTA (8.44%). Furthermore, the identification of proteins in 20-G revealed that the decrease in OTA content was mainly a result of the action of peroxidase, and validation tests were carried out. By analyzing the degradation products of OTA, OTα and phenylalanine with lower toxicity were obtained. Animal experiments showed that the intervention of yeast 20-G reduced the damage and adverse effects caused by OTA toxicity to the mice. The present study demonstrates the mechanism of OTA removal by 20-G and the toxicity of OTA was reduced by peroxidase in 20-G. © 2023 Society of Chemical Industry.

Race, pigmentation, and the human skin barrier-considerations for dermal absorption studies.

A functional human skin barrier is critical in limiting harmful exposure to environmental agents and regulating the absorption of intentionally applied topical drug and cosmetic products. Inherent differences in the skin barrier between consumers due to extrinsic and intrinsic factors are an important consideration in the safety assessment of dermatological products. Race is a concept often used to describe a group of people who share distinct physical characteristics. The observed predisposition of specific racial groups to certain skin pathologies highlights the potential differences in skin physiology between these groups. In the context of the human skin barrier, however, the current data correlating function to race often conflict, likely as a consequence of the range of experimental approaches and controls used in the existing works. To date, a variety of methods have been developed for evaluating compound permeation through the human skin, both in vivo and in vitro. Additionally, great strides have been made in the development of reconstructed human pigmented skin models, with the flexibility to incorporate melanocytes from donors of different race and pigmentation levels. Together, the advances in the production of reconstructed human skin models and the increased adoption of in vitro methodologies show potential to aid in the standardization of dermal absorption studies for discerning racial- and skin pigmentation-dependent differences in the human skin barrier. This review analyzes the existing data on skin permeation, focusing on its interaction with race and skin pigmentation, and highlights the tools and research opportunities to better represent the diversity of the human populations in dermal absorption assessments.

Fabrication of an electrochemical sensor based on molecular imprinting technology for detecting elemene

This paper presents the fabrication of an electrochemical sensor based on molecular imprinting technology for the detection of elemene, a bioactive compound with various pharmacological activities. The sensor was prepared by electrochemically polymerizing acrylamide and N,N-methylenebisacrylamide in the presence of dopamine hydrochloride and phytic acid as functional monomers, with elemene as the template molecule. The resulting molecularly imprinted polymer film on the glassy carbon electrode exhibited specific recognition sites for elemene. The sensor's electrochemical performance was systematically investigated using cyclic voltammetry and electrochemical impedance spectroscopy. The sensor showed excellent selectivity, sensitivity, stability, and reproducibility for elemene detection. The optimized sensor parameters, such as the number of polymerization cycles and elution time, were determined. The sensor exhibited a linear response to elemene in the concentration ranges of 10 μM to 0.1 mM and 50 nM to 10 μM, with a detection limit of 2.7 nM. The proposed electrochemical sensor offers a rapid, label-free, and selective detection platform for elemene, eliminating the need for complex sample preparation and expensive labeling reagents. It has the potential for application in quality control, safety assessment, and therapeutic efficacy evaluation of elemene-containing products.

Development and application of an interactive generic physiologically based pharmacokinetic (igPBPK) model for adult beef cattle and lactating dairy cows to estimate tissue distribution and edible tissue and milk withdrawal intervals for per- and polyfluoroalkyl substances (PFAS)

Humans can be exposed to per- and polyfluoroalkyl substances (PFAS) through dietary intake from milk and edible tissues from food animals. This study developed a physiologically based pharmacokinetic (PBPK) model to predict tissue and milk residues and estimate withdrawal intervals (WDIs) for multiple PFAS including PFOA, PFOS and PFHxS in beef cattle and lactating dairy cows. Results showed that model predictions were mostly within a two-fold factor of experimental data for plasma, tissues, and milk with an estimated coefficient of determination (R2) of >0.95. The predicted muscle WDIs for beef cattle were <1 day for PFOA, 449 days for PFOS, and 69 days for PFHxS, while the predicted milk WDIs in dairy cows were <1 day for PFOA, 1345 days for PFOS, and zero day for PFHxS following a high environmental exposure scenario (e.g., 49.3, 193, and 161 ng/kg/day for PFOA, PFOS, and PFHxS, respectively, for beef cattle for 2 years). The model was converted to a web-based interactive generic PBPK (igPBPK) platform to provide a user-friendly dashboard for predictions of tissue and milk WDIs for PFAS in cattle. This model serves as a foundation for extrapolation to other PFAS compounds to improve safety assessment of cattle-derived food products.