Approaches for setting occupational exposure limits in the pharmaceutical industry.

The use of pharmaceutical drugs has provided a cure for many diseases. However, unintended exposure to drugs in the manufacturing workplace can cause significant health hazards to workers. It is important to protect the workforce from these deleterious effects by limiting exposure to an acceptable level, the occupational exposure limit (OEL). OEL is defined as airborne concentrations (expressed as a time-weighted average for a conventional 8-h workday and a 40-h work week) of a substance to which nearly all workers may be repeatedly exposed (for a working lifetime) without adverse effects. Determination of OELs has become very challenging over time, requiring an overall assessment of the preclinical and clinical data of the drug being manufactured. Previously, to derive OEL values, toxicologists used animal no-observed-adverse-effect level (NOAEL) data, which have been replaced with the overall assessment of animal and human data, placing a higher emphasis on human health-based data. A major advantage of working with human pharmaceuticals is that sufficient clinical data are available for them in most cases. The present manuscript reviews the latest knowledge regarding the derivation of occupational exposure limits as health-based exposure limits (HBELs) for pharmaceuticals. We have provided examples of OEL calculations for various drugs including levofloxacin (CAS No. 100986-85-4), dienogest (CAS no. 65928-58-7), and acetylsalicylic acid (ASA, CAS no. 50-78-2) using human data. This report will benefit professionals in the OEL domain in understanding this highly important, growing, and challenging field.

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

BACKGROUND: 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. OBJECTIVE: The objective was to present a comprehensive review of available scientific knowledge for derivation of PDE. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Three-dimensional finite element analysis to evaluate biomechanical effects of different alveolar decortication approaches on rate of canine retraction.

INTRODUCTION: The aim of this study was to compare different corticotomy approaches and determine their biomechanical effects on rate of canine displacement when compared to conventional orthodontics. METHOD: Three-dimensional Finite Element Models with conventional non-corticotomy approach (model 1) and three corticotomy approaches ensuing buccal and palatal vertical cuts (model 2), interseptal bone reduction (model 3), buccal vertical cuts (model 4) were fabricated. Displacement of the canine and von Mises stresses in the canine and trabecular bone were calculated and compared under a distal retraction force of 1.5N. RESULTS: The maximum displacement of canine with minimum anchorage loss was seen in model 3 followed by model 2, model 4 and model 1. The maximum equivalent (von Mises) stress was concentrated mainly on the distal side of canine in model 3 and had a uniform distribution of stresses on entire root surface. CONCLUSIONS: Corticotomy approaches effectively accelerated maxillary canine retraction, exhibiting twice the rate of canine movement with minimum anchorage loss when compared to non-corticotomy approach. Corticotomy with interseptal bone reduction was most effective in terms of canine displacement and stress distribution.

Comparison of conventional methods of simultaneous intrusion and retraction of maxillary anterior: a finite element analysis.

OBJECTIVE: To study the biomechanical effects of the three-piece intrusion arch and Kalra simultaneous intrusion and retraction arch (K-SIR) on simultaneous intrusion and retraction of maxillary anterior teeth. DESIGN: Three-dimensional analysis of stresses and displacement of the anterior and posterior teeth with the three-piece intrusion arch and K-SIR arch was done using the finite element method (FEM). SETTING: Department of Orthodontics, Surendera Dental College and Research Institute, India. MATERIAL AND METHODS: For this investigation, the geometric model of the maxilla was constructed using a computed tomography scan. 0.022 × 0.028-inch MBT brackets and molar tubes were modelled, with the specified tip and torque values for all maxillary teeth. The wire components for the three-piece intrusion arch and K-SIR arch were modelled initially as a line diagram and then converted to three dimensional models. The material characteristics which include the Young's modulus and Poisson's ratio were assigned. After defining the boundary conditions, force systems were applied as per design. The analysis was carried out using ANSYS Version 12.1 software. The von Mises stress, principal stress on PDL and alveolar bone, change in the inclination of incisors and initial displacement of the teeth in bucco-palatal, mesio- distal and vertical direction were analysed. RESULTS: Stresses in cortical bone were greater than cancellous. Both modalities showed intrusion of the anterior teeth, although this was slightly more in the three- piece intrusion arch. On studying the principal stresses in the PDL, the three-piece intrusion arch displayed uniform stress distribution compared to K-SIR arch. CONCLUSION: The FEM cannot reflect actual biological responses within the human body to orthodontic forces but based on these findings, the three-piece intrusion arch showed better stress distribution and controlled tooth movement than the K-SIR arch.

Predicting toxicities in humans by nonclinical safety testing: an update with particular reference to anticancer compounds.

The sensitivity of the various preclinical models used to predict toxicity in humans varies. In this review, we analyze the various models used to predict safety in drug discovery and development with a view to understanding their translational value in humans. Twenty recently approved anticancer drugs were studied and the available nonclinical and clinical adverse effects information available from the US Food and Drug Administration (FDA) was analyzed. We found that gastrointestinal and hematopoietic toxicities in humans were predicted to the maximum extent by nonclinical models, whereas respiratory, integumentary, renal, nervous, hepatic, and cardiovascular were moderately predicted. Ocular, endocrine, and musculoskeletal toxicities were poorly predicted while lymphatic and immune toxicities were difficult to predict.

Drug safety testing paradigm, current progress and future challenges: an overview.

Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

Assessment of the sensitizing potential of textile disperse dyes and some of their metabolites by the loose-fit coculture-based sensitization assay (LCSA).

Certain textile disperse dyes are known to cause allergic reactions of the human skin. Here, we examined 8 disperse dyes and 7 products of azo-cleavage of these dyes in an in vitro assay. We used the loose-fit coculture-based sensitization assay (LCSA) of primary human keratinocytes and of allogenic dendritic cell-related cells for combined testing of the sensitizing and irritative properties of these substances. The obtained data were compared to data generated in a modified version of the local lymph node assay by our working group. Disperse Blue 1 (DB1), p-nitroaniline (pNA) and p-aminoacetanilide (AAA) showed no sensitizing potential under our experimental conditions. Disperse Blue 124 (DB124), Disperse Yellow 3 (DY3), Disperse Orange 37/76 (DO37), Disperse Blue 106 (DB106), Disperse Red 1 (DR1), 2-amino-p-cresol (ApC), Disperse Orange 3 (DO3) and 2,6-dichloro-4-nitroaniline (DCh) were categorized as extreme sensitizers. Para-phenylenediamine (pPD) was categorized as strong sensitizer, and 2-amino-5-nitrothiazole (ANT) and 2-(N-ethylanilino)-ethanol (EAE) as weak sensitizers. All dyes, except for DB1, and ApC turned out to be strong irritants. DB1, ANT and DCh showed only weak irritative potential. PPD, pNA, EAE and AAA did not show any irritative effect at the concentration range tested. These results correlate with data derived from the modified version of LLNA and human data. Therefore, the LCSA represents a suitable test system to simultaneously analyse two crucial properties of substances relevant for allergy induction.

Evaluation of biotechnology-derived novel proteins for the risk of food-allergic potential: advances in the development of animal models and future challenges.

Increasing concern from the public about the safety of genetically modified food has made critical to have suitable methods for recognizing associated potential hazards. Hierarchical approaches to allergenicity determination were proposed, and these include evaluation of the structural and sequence homology and serological identity of novel proteins with existing allergens, measuring the resistance to proteolytic digestion and assessment of sensitizing potential using animal models. Allergic individuals have a predisposed (i.e. atopic) genetic background, and a close resemblance to this setup is therefore desirable in animal models, which is possible by using a strain of an animal species that is prone for allergic disorders. So far, none of the animal model has been validated for the purpose of hazard identification in the context of safety assessment. However, the available knowledge suggests that the judicious use of an appropriate animal model could provide important information about the allergic potential of novel proteins. This paper provides an up-to-date review of the progress made in the field of development of in vivo models in this direction and the further goals that have to be achieved.

Ammonium perfluorooctanoate substantially alters phenotype and cytokine secretion of human monocyte-derived dendritic cells in vitro.

Perfluoroalkyl carboxylic acids (PFCA) are commercially used for their surfactant properties combined with chemical and thermal stability. Differentiation of peripheral monocytes to immature dendritic cells (DCs) in the presence of the PFCA, ammonium perfluorooctanoate (APFO, 200 microM) led to a considerably increased expression of CD86 and HLA-DR on immature DCs. However, these phenotypic changes were not reflected by an increased T cell-stimulatory capacity of the cells. Notably, activated, fully mature APFO-treated DCs secreted significantly less IL-12 and IL-10 than control cells. Thus, APFO at non-cytotoxic concentration affects the phenotype and cytokine secretion of human DCs.

Appraisal of the sensitising potential of orally and dermally administered mercaptobenzothiazole by a biphasic protocol of the local lymph node assay.

Mercaptobenzothiazole (MBT) is used while manufacturing natural rubber products. Our study deals with assessing its allergenic potential following dermal and oral routes of exposure, using a biphasic local lymph node assay (LLNA). Female Balb/c mice were treated with MBT (dermally 3, 10, 30% concentrations in DMSO; orally 1, 10, 100 mg/kg doses in corn oil) on the back (dermal study) or through oral administration (oral study) on days 1-3 followed by auricular application of 3, 10 and 30% concentrations, respectively, on days 15-17. End points determined on day 19 included ear thickness, ear punch weight, lymph node weight, lymph node cell count, and lymphocyte subpopulations (CD4+, CD8+, CD45+). After dermal application of 3% or 10% solution, a significant increase in cell count and lymph node weight along with significant decrease in CD8+ cells was observed. After initial oral administration of 1 mg/kg, we noticed a significant amplification in cell count. Following oral administration of 10 mg/kg, we observed a similar increase in cell count and lymph node weight. The results of our study show that the modified biphasic LLNA protocol can be used to study the sensitising potential of a compound also following the oral route of exposure.

Investigation of the sensitising and cross-sensitising potential of textile dyes and beta-lactam antibiotics using a biphasic mice local lymph node assay.

We used a modified protocol of the murine local lymph node assay (LLNA) to study the cross-sensitising potential of (a) textile dye disperse yellow 3 and its metabolite 2-amino-p-cresol, (b) two antibiotics, penicillin G and cefotiam. The test substances were applied in a biphasic manner, i.e. first on the shaved skin of the back followed by application on the dorsal side of the ears after 2 weeks. The end-points analysed included thickness and weight of an ear-biopsy, weight and cell number of the draining lymph node, and lymphocyte cell surface markers analysed by flow-cytometry. Disperse yellow 3 and its metabolite significantly altered the various end-points at both the tested concentrations (0.5 and 1%), thus demonstrating the sensitising potential of the two substances. The cross-sensitisation study showed significant modulation in the tested variables in the treated group as compared to the control, signifying cross-sensitisation potential of the two substances. Penicillin G and cefotiam showed significant changes in various end-points, pointing towards their sensitising potential. However, even at 50% concentration of the beta-lactams no significant change in any end-point indicating absence of cross-reactivity of the antibiotics was noticed. We conclude that a biphasic, modified protocol of the LLNA is a suitable approach to test for a cross-reactivity potential of two related compounds.