Permitted Daily Exposure Research Articles

The toxicological analysis of problematic and sophisticated elements (Ni, Cr, and Se) in Food for Special Medical Purposes (FSMP) using in pharmacotherapy and clinical nutrition for oncological patients available in Polish pharmacies

This study focuses on FSMPs for oncologic patients, specifically analyzing the toxicological profiles of nickel (Ni), chromium (Cr), and selenium (Se) within these products available in Polish pharmacies. The presence of these elements was quantified using inductively coupled plasma mass spectrometry (ICP-MS). Results indicated variations in the concentrations of Ni, Cr, and Se across different FSMP samples, with some products exceeding the acceptable limits set by regulatory guidelines. The study highlights the potential health risks associated with nickel exposure, including dermatitis and carcinogenesis, and the complex roles of chromium and selenium, which can be both beneficial and harmful depending on their levels. Our findings reveal significant variability in the elemental content across different FSMP products, i.e.: Ni: 0.155–25.488 μg/portion, Cr: 0.076–28.726 μg/portion and Se: 0.083–20.304 μg/portion). Notably, selenium levels in FSMPs showed considerable discrepancies compared to manufacturers' declarations, averaging only about 20% of the stated values. Regulatory assessments based on the Acceptable Daily Intake (ADI) and Permitted Daily Exposure (PDE) descriptors indicated that the estimated weekly intake of Ni, Cr, and Se from these FSMPs did not exceed the provisional tolerable weekly intake (PTWI) values. However, the highest Ni content was 30.58% of the PTWI, raising concerns about potential health risks, including dermatitis and carcinogenesis. The results for Cr underscored the necessity for careful monitoring due to its potential toxic effects. Selenium, despite its essential role, showed levels inadequate to meet the Recommended Dietary Allowance (RDA), potentially impacting its intended health benefits.

PHYSICAL ASSESSMENT AND ATOMIC ABSORPTION SPECTROPHOTOMETRIC ANALYSIS OF CADMIUM AND LEAD IN TWENTY-FIVE BRANDS OF CIPROFLOXACIN TABLETS MARKETED IN LAGOS, NIGERIA.

Ciprofloxacin is a second-generation broad-spectrum antibiotic of the fluoroquinolone class, highly effective against many bacteria. Several brands of this drug class are marketed for public consumption; hence, it has placed the public in a confused state about the best brands with suitable physical characteristics and safe oral consumption. Additionally, the adverse effects of heavy metal accumulation in drugs for oral use have made it essential to quantify the amount of such heavy metals present. Evaluating the physical quality, elemental analysis identity, and concentration of cadmium and lead in twenty-five brands of ciprofloxacin tablets marketed in Lagos, Nigeria, is the aim of this study. The physical assessment of the tablets was then methodologically evaluated for these parameters; Uniformity of weight, Hardness, Friability, and Disintegration tests. Determining the amount of Cadmium and Lead with the Atomic Absorption Spectrophotometer (AAS) and evaluating using the Permitted Daily Exposure (PDE). Among all the brands of Ciprofloxacin tablets analyzed, 96 % passed the Uniformity of weight test, 52 % passed the Hardness test, 96 % passed the Friability test, and 96 % passed the disintegration test while 2 % passed the test according to the Permitted Daily Exposure (PDE) to Cadmium. 72 % passed the test according to the Permitted Daily Exposure (PDE) to Lead. The brands that passed the physical tests have good quality and correct physical characteristics. Cadmium and lead are of no benefit to humanity in the body and because they are not easily eliminated from the body, their buildup can put people at risk for mental retardation in children, dementia, kidney damage, nerve damage, infertility, high blood pressure, and cancer at high exposure levels. Keywords: Ciprofloxacin, Permitted Daily Exposure, Physical characteristics, Atomic Absorption Spectrophotometer, Cadmium, Lead

Elemental impurities determination in bromhexine hydrochloride injections

Elemental impurities in drug products have no therapeutic effect and may pose toxicological concerns, therefore it is urgent to assess the safety of elements especially in parenteral exposure drug. In the present work, a high throughput inductively coupled plasma mass spectrometry (ICP-MS) method was developed for the quantitative determination of 31 elemental impurities in bromhexine hydrochloride injections from 9 manufactures. The method was successfully validated for linearity, accuracy, precision, stability, the LOD and the LOQ according to the United States Pharmacopeia (USP) < 233 > . All the elemental impurities determined were below the permitted daily exposure (PDE) limits proposed by the International Council for Harmonisation (ICH). However, significant differences were found between different manufactures’ products for some elements, particularly for Al, As, B, Ba and Zn. Besides, discussions considering potential risks of elemental contamination were also presented.

Comparison of the acceptable surface limits derived from the skin sensitization potency for workers and swab residue limits determined from the permitted daily exposure derived from the systemic effects.

Allergic contact dermatitis is a common occupational and environmental health problem and setting of health-based exposure limits (HBELs) to prevent induction of skin sensitization is strongly desired. When manufacturing pharmaceuticals in a shared facility, cleaning validation using surface residue levels (SRLs) derived from permitted daily exposures (PDEs) is conducted to avoid cross-contamination from the perspective of protecting patients; however, it is unclear whether the SRLs are sufficient to prevent induction of skin sensitization for workers as well. In this study, we compared acceptable surface limits (ASLs) derived from acceptable exposure levels (AELs) based on EC1.6 obtained from local lymph node assay (LLNA): BrdU-ELISA for occupational risk management of skin sensitizers with PDE-based SRLs. ASLs for 1,4-phenylenediamine (GHS skin sensitization sub-category 1A), isoeugenol (sub-category 1A), and methyl methacrylate (sub-category 1B) were compared with SRLs based on the PDEs derived from their systemic effects. The results yielded an SRL for 1,4-phenylenediamine (PDE: 0.8 mg/day) of 30 mg/100 cm2, almost 1,000 times higher than ASL (0.031 mg/100 cm2) derived from its skin sensitization potency. SRL for isoeugenol (PDE: 3.1 mg/day) was 130 mg/100 cm2, over 500 times higher than ASL (0.18 mg/100 cm2). For methyl methacrylate (PDE: 5 mg/day) as well, SRL (200 mg/100 cm2) was higher, but it was within 20 times the ASL (10 mg/100 cm2). These results showed that ASL-based risk management is extremely important especially for strong sensitizers classified as GHS sub-category 1A for occupational skin sensitization risk management.

LP-08 Permitted Daily Exposure (PDE) assessment of data-poor pharmaceutical impurities using read-across (RA) approach: A case study with selected siloxane compounds

LP-08 Permitted Daily Exposure (PDE) assessment of data-poor pharmaceutical impurities using read-across (RA) approach: A case study with selected siloxane compounds

Considerations for Permitted Daily Exposure Calculation for Contaminants in Medicinal Products Manufactured in Shared Facilities

The manufacture of different medicinal products in shared facilities creates a risk of cross-contamination. One of the approaches to select the limits for possible contaminants is based on calculating the permitted daily exposure (PDE), i.e. the dose of an active pharmaceutical ingredient or any other substance contaminating a medicinal product that will not be associated with any adverse events in a human in the case of lifetime exposure. The aim of this study was to provide practical guidance on selecting adjustment factors for calculating PDEs to establish limits for potential contaminants in multi-purpose pharmaceutical facilities. The authors analysed the regulatory requirements and literature needed to establish critical effects of contaminants, outlined possible assumptions in the use of quantitative indicators for measuring toxicity, and described the relationship between the PDE and other indicators of the safety of chemical compounds for human health. The article presents an example of PDE calculation for an investigational hypoglycemic medicinal product using a limited amount of open-source literature data. Thus, the article demonstrates the role of information on the primary pharmacodynamic effects of medicinal products in the assessment of their critical effects, which is necessary to implement the most conservative approaches to PDE calculation. The example of PDE calculation presented in the article may be used to assess cross-contamination risks associated with non-dedicated manufacturing facilities.

Structure elucidation and toxicological evaluation of cyclic Polyethersulfone oligomers present in extracts of membrane filters

Polyethersulfone (PES) is a widely used polymer in consumer and technical products. An important application is PES membranes used in the biopharmaceutical industry for sterilizing-grade filtration and for filtration of food and beverages. For both uses, detailed information about migrating compounds that can be extracted from the polymeric material into a liquid must be gathered. In the pharmaceutical industry, comprehensive extractables studies are required for contact materials, and the data is used in the qualification of the process equipment. PES is generated via polycondensation, which forms cyclic oligomers as a by-product of the reaction. However, no structural information is available for these cyclic oligomers so far. In this publication, we present the analytical determination of PES cyclic oligomers. Their presence in extracts of PES membrane filters is confirmed. The structure of the PES cyclic trimer is elucidated by X-ray and NMR investigation, obtained as crystals from the sublimation of the PES raw material. A strategy is shown to assess the toxicity of such cyclic oligomers and to derive a permitted daily exposure (PDE). The data will reduce the levels of unknowns in extractables and leachables screenings and supports the risk assessment of PES sterile filters.

Application of a novel exposure limit approach for co-exposure of ‎chemicals: a field study by in-vitro design

ABSTRACT This study has suggested an occupational exposure limit (OEL) based on the co-exposure approach in an iron-foundry industry. Respirable dust was collected in an iron casting industry using the NIOSH 0600 method. The DNA damage was obtained by comet assay. The lower confidence interval of the benchmark dose (BMDL) was employed for exposure limit evaluation. The estimated BMDL of the cell line was extrapolated to human subjects. Based on the Hill model, a BMDL 1.65 µg for chemical mixture has been estimated for the A549 cell line. According to uncertainty factors, permitted daily exposure (PDE) was predicted in humans. However, PDE of 3.9 μg/m3 was specified as the time-weighted average limit for toxic respirable dust in the casting industry. In this study, OEL for active respirable dust in the casting industry has been proposed. The industry-based standard for active respirable dust has been proposed for better management of co-exposure.

Challenges in setting permitted daily exposure limits for pharmaceuticals: A review

When more than one drug is manufactured at a shared facility or equipment in pharmaceutical manufacturing, the potential carry-over of the retained residue of existing drug product on product contact parts of the equipment to the next product can be a source of cross contamination. Permitted daily exposure (PDE) is derived based on the complete nonclinical and clinical data available and is a dose that is unlikely to cause adverse effects if an individual is exposed, by any route, at or below this dose every day over a lifetime. The objective was to present a comprehensive review of available scientific knowledge for derivation of PDE. PubMed and ScienceDirect databases were searched using keywords "PDE" and "pharmaceuticals" and all the relevant literature up to March 2021 was reviewed. We have also calculated PDEs for Tobramycin (CAS No. 32986-56-4) and Acetyl Salicylic Acid (ASA, CAS No. 50-78-2). This research will be useful for scientists working in the PDE domain. The given examples emphasize the importance of use of human data in calculating PDE. The duty of the risk assessor entrusted with setting PDEs is to derive a data driven, scientifically justified value that is safe for patients, while avoiding unjustified conservativeness that puts unnecessary burden on manufacturing.

Study and Determination of Aluminum in Dextran 40 Glucose Injection by ICP-MS

Background: Aluminum (Al) is classified as other elements by ICH, and its permitted daily exposure (PDE) has not been established. As it might cause compromised renal function, guidelines, regional regulations and practices need to be addressed. According to the United States Pharmacopeia 41 and the Japanese Pharmacopoeia 17, the aluminum content of large-volume parenterals (LVPs) used in total parenteral nutrition (TPN) therapy must not exceed 25 ng mL-1. Therefore, the package insert of LVPs used in TPN therapy must state the content of aluminum. Objective: A new microwave assisted acid digestion pretreatment together with inductively coupled plasma mass spectrometry (ICP-MS) method was developed for the determination of aluminum content in Dextran 40 Glucose Injection. The method was successfully applied for quality evaluation of commercial Dextran 40 Glucose Injection. Methods: Samples were digested by a mixture of nitric acid and hydrochloric acid, with the assistance of microwave. After that, ICP-MS in KED mode was employed to analyze the samples. Results: The method showed a good linearity (r2=0.9999) within the range of 2~100 ng mL-1, with the limit of detection and quantitation of 0.482 ng mL-1 and 1.61 ng mL-1, respectively. A good precision was obtained with relative standard deviation (RSD) of 8.8% (n=6). The spike recoveries with low, middle and high Al content in 9 sample were 102.2%~107.4%. Conclusion: The developed method was successfully applied for the analysis of Al content in 44 batches of Dextran 40 Glucose Injection produced by 9 pharmaceutical companies from domestic or international enterprises. The Al content of Dextran 40 Glucose Injection varied greatly between different enterprises or different batches. Meanwhile, among total of 44 batches, the Al content in 3 batches of Dextran 40 Glucose Injection exceeded the limitation of 25 ng mL-1, which might cause potential safety problems.

Study of the compatibility of oral magnesium oxide preparations sold in Japan with the ICH-Q3D guideline for elemental impurities.

Magnesium oxide has been widely used as an antacid and constipation remedy. Currently in Japan, magnesium oxide preparations manufactured by five medical companies are marketed as prescribed generic drugs. In this study, we focused on metal elemental impurities present in 330 mg magnesium oxide tablets manufactured by each of these companies. The content of such impurities was determined by atomic absorption spectrometry and inductively coupled plasma mass spectrometry. We confirmed whether the content conformed to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Guideline for Elemental Impurities (ICH-Q3D) based on the 30% control threshold. The content of these impurities varied among the five products (preparations A-E), but in all cases met the oral permitted daily exposure (PDE) criteria stipulated in ICH-Q3D. In 5 lots of preparation C and all lots of preparation D, the equivalent cadmium (Cd) intake for a daily maximum dosage of 2 g was higher than the 30% control threshold of 1.5 µg/day. By cluster analysis, preparations A-E were classified into preparations A + B and C + D + E and/or preparations A + B, C + D and E. The present study showed that all 5 preparations sold in Japan meet the PDE value standard of ICH-Q3D, and that preparations A and B meet the 30% control threshold. It is important that for preparations failing to meet the criteria, further improvements need to be sought, and impurities in magnesium oxide preparations need to be monitored to ensure their safety.

Establishment and Validation of an ICP-MS Method for Simultaneous Measurement of 24 Elemental Impurities in Ubenimex APIs According to USP/ICH guidelines

Background: To control the potential presence of heavy metals in pharmaceuticals, the United States Pharmacopeia (USP) and International Conference on Harmonization (ICH) have put forth new requirements and guidelines. USP &lt;232&gt; and ICH Q3D specify 24 elemental impurities and their concentration limits in consideration of the permitted daily exposure (PDE) of different drug categories (oral, parenteral and inhalation). while USP &lt;233&gt; describes more information about sample preparation and method validation procedure. Objective: To establish and verify an ICP-MS method for the determination of 24 elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Ph, Ru, Se, Ag, Pt, Li, Sb, Ba, Mo, Cu, Sn, Cr) in ubenimex APIs according to USP/ICH guidelines. Method: Samples were analyzed by ICP-MS after direct dissolution in diluted acid solution. All elements were detected in He/HEHe mode (except for Li, which was in No gas mode). Results: The spiked recoveries were within 80-120% except Hg (79.4% at 0.5J level in HEHe mode) and Cd (121.9% at 0.5J level in HE mode). The RSD of repeatability (N = 6) for all elements were &lt; 7.0% and intermediate precision (N = 12) were &lt; 9.0%. The correlation coefficients of linear (R) for 24 elements were all &gt; 0.998. The limits of detection (LOD) were &lt; 1 ng/mL except that Ni was 1.23 ng/mL in HEHe mode. The contents of 24 elements in 3 batches of samples were significantly lower than the actual target limit of ICH, while the highest content of Pd did not exceed 10 μg/g. Conclusion: The established method was proved to be simple, sensitive and accurate. It successfully applied to the elemental impurity determination in 3 batches of ubenimex APIs from different manufactories. This method also provided technical guidance for determination of multiple elements in pharmaceutical products.

Determination of Cleaning Limits Considering Toxicological Risk Evaluation to Minimize the Risk of Cross Contamination.

The historical approaches that have been used to establish cleaning validation acceptance limits should be updated to recent approaches to prevent cross contamination. In the present investigation, a cleaning method was validated using high performance liquid chromatography. Method modification critical parameters including spiking, swab sampling from PVC, Stainless Steel, and Polyethylene, extraction technique from swab, solubility, potency, toxicity (LD50), and improvement of limit of detection (LOD) of the method through analytical method validation were studied. In addition, roughness, mechanical and electro-polishing, consideration of dosage form as a quantitative factor, acceptable daily exposure (ADE), and permitted daily exposure (PDE) in the worst-case determination were considered in the study. The method was validated based on USP and ICH guidelines for specificity, limit of detection, limit of quantitation, precision, accuracy, linearity, and range. Linear regression analysis of data for the calibration plot in the range of 7.43, 10.89, 21.78, 43.56, 87.12 µg/mL, and relative standard deviation (R.S.D.) found to be 0.5, 0.4, 0.2, and 0.2, respectively with correlation coefficient of R2 = 0.999997. The LOD and the limit of quantitation (LOQ) were 2.23 and 7.43 µg/mL, respectively. Good recoveries in the range of 73.65-81.20%, and precision with relative standard deviation values lower than 15% have been obtained. The proposed method developed for cleaning validation is specific, precise, and useful for determination of cleaning acceptance limits using health-based limit and Quality Risk Management to develop an appropriate cleaning program for engineering design, safety of patients, and worker protection.

Filling data gap for nicotinic acid, nicotinate esters and nicotinamide for the determination of permitted daily exposure by a category approach.

This study aimed to obtain necessary toxicological data using experimental and computational methods for the calculation of a common permitted daily exposure (PDE) which can be relevant for nicotinic acid and its esters and nicotinamide according to European Medicines Agency Guideline on setting health-based exposure limits. PDE calculation is mainly based on critical toxicological endpoints. During this procedure, critical toxicological endpoints data of an active pharmaceutical ingredient (API) may not be able to find satisfactorily. Hence, using toxicological data for another API that has a similar chemical structure can be a useful way. In this study, toxicological endpoints of nicotinic acid and its esters and nicotinamide were evaluated. Then, the data gaps in the toxicological endpoints were filledusing the read-across approach. Based on the current existing data, nicotinic acid and its esters and also nicotinamide are not genotoxic and do not have skin sensitization potential. These compounds do not present a concern for carcinogenicity and developmental/reproductive toxicity. Based on these critical endpoints and available experimental data, the final PDE of 10mg/day was calculated for all category members. Our study showed the utility of the read-across for PDE calculation of APIs with experimental toxicological data gap.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

The purpose of the present investigation is to analyze the in vivo genotoxicity dose–response data of ethylene oxide (EO) and the applicability of the derived point‐of‐departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chromosomal damage in various tissues were considered the most relevant for assessing risk from EO, since these effects are likely to contribute to adverse health consequences in exposed individuals. The PoD estimates were screened for precision and the values were divided by data‐derived adjustment factors. For gene mutations, the lowest PDE was 285 parts per trillion (ppt) based on the induction of lacI mutations in the testes of mice following 48 weeks of exposure to EO. The corresponding lowest PDE value for chromosomal mutations was 1,175 ppt for heritable translocations in mice following 8.5 weeks of EO exposure. The lowest PDE for chromosomal aberrations was 238 ppt in the mouse peripheral blood lymphocytes following 48 weeks of inhalation exposure. The diverse dose–response data for EO‐induced genotoxicity enabled the derivation of PoDs for various endpoints, tissues, and species and identified 238 ppt as the lowest PDE in this retrospective analysis.

Safety of medicinal comfrey cream preparations (Symphytum officinale s.l.): The pyrrolizidine alkaloid lycopsamine is poorly absorbed through human skin

European Union guidelines indiscriminately discuss a permitted daily exposure (PDE) for pyrrolizidine alkaloids (PA) of up to 0.007 μg/kg body weight for oral and for topical exposure to herbal medicinal products. In this study, lycopsamine served as a model substance for measuring the extent of skin permeation of PAs following the application of a spiked comfrey cream (Symphytum officinale s.l.) to abdominal skin from human donors in Franz diffusion cells. PAs could be excluded in the non-spiked cream with a limit of detection of 8 μg/kg. Only small amounts of the applied quantity of lycopsamine had migrated through the skin sample into the receptor cell side of the diffusion cell after 24 h. In five of six diffusion cells, there was no detectable lycopsamine within the skin and only 0.6 ± 0.4% of the applied dose in the receptor fluid. The theoretical skin penetration of 4.9% of the applied quantity of lycopsamine largely resulted from the worst case approach of assuming the presence of at least a quantity corresponding to the limit of detection – the true penetration is probably considerably lower. Even with the worst-case calculation, the currently discussed guidelines on PA overestimate the risk related to topical preparations.

Permitted Daily Exposure Values: Application Considerations in Toxicological Risk Assessments.

Permitted daily exposure (PDE) values are used by some toxicologists to support the safety qualification of various types of impurities found in a drug substance (DS) or drug product (DP). Permitted daily exposure values are important tools for the toxicologist, but one must be aware of their limitations to ensure that they are used appropriately and effectively in the risk assessment process. First, a toxicologist must always perform a comprehensive analysis of all available animal and human safety data for an impurity, including identifying any data gaps that may exist. Second, if adequate data are available and there are no genotoxicity concerns, an appropriate well-designed repeat-dose toxicity study in animals should be chosen to calculate the PDE. It is important to note that PDE values qualify general systemic toxicity and not necessarily local toleration end points such as irritation and sensitization that are more concentration than dose dependent. In addition, a PDE value calculated from a general toxicity study in animals may not necessarily qualify for reproductive toxicology end points. Lastly, PDE values should never be thought of as analytical limits for or acceptable levels of an impurity in a DS or DP, as this ignores quality considerations. Using safety information from several chemicals as proxy impurities, this article serves as an educational primer to facilitate a better understanding of the development and use of PDE values in the risk assessment process.

Review of Elemental Impurities in Pharmaceuticals Arena

Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in the synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. The main objective of the International Conference on Harmonization (ICH) (Q3D) guideline applies to new finished drug products and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides. This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components, or blood derivatives, including plasma and plasma derivatives. The evaluation of the toxicity data for potential elemental impurities; the establishment of a permitted daily exposure (PDE) for each element of toxicological concern; application of a risk-based approach to control elemental impurities in drug products. Different analytical techniques for elemental impurities detection: flame atomic absorption spectrometry (FAAS), graphite furnace atomic absorption spectrometry (GFAAS), atomic fluorescence spectrometry, X-ray fluorescence spectrometry (XRF), instrumental neutron activation analysis (INAA), inductively coupled plasma-atomic emission spectroscopy (optical emission spectroscopy, ICP-OES), inductively coupled plasma mass spectrometry (ICP-MS), and microwave plasma atomic emission spectrometry (MP-AES).

Development and evaluation of a harmonized whole body physiologically based pharmacokinetic (PBPK) model for flutamide in rats and its extrapolation to humans

By their definition, inadvertent exposure to endocrine disrupting compounds (EDCs) intervenes with the endocrine signalling system, even at low dose. On the one hand, some EDCs are used as important pharmaceutical drugs that one would not want to dismiss. On the other hand, these pharmaceutical drugs are having off-target effects and increasingly significant exposure to the general population with unwanted health implications. Flutamide, one of the top pharmaceutical products marketed all over the world for the treatment of prostate cancer, is also a pollutant. Its therapeutic action mainly depends on targeting the androgen receptors and inhibiting the androgen action that is essential for growth and survival of prostate tissue. Currently flutamide is of concern with respect to its categorization as an endocrine disruptor.In this work we have developed a physiologically based pharmacokinetic (PBPK) model of flutamide that could serve as a standard tool for its human risk assessment. First we built the model for rat (where many parameters have been measured). The rat PBPK model was extrapolated to human where the re-parameterization involved human-specific physiology, metabolic kinetics derived from in-vitro studies, and the partition coefficient same as the rat model. We have harmonized the model by integrating different sets of in-vitro, in-vivo and physiological data into a PBPK model. Then the model was used to simulate different exposure scenarios and the results were compared against the observed data. Both uncertainty and sensitivity analysis was done.Since this new whole-body PBPK model can predict flutamide concentrations not only in plasma but also in various organs, the model may have clinical applications in efficacy and safety assessment of flutamide. The model can also be used for reverse dosimetry in the context of interpreting the available biomonitoring data to estimate the degree to which the population is currently being exposed, and a tool for the pharmaceutical companies to validate the estimated Permitted Daily Exposure (PDE) for flutamide.