Human Biomonitoring (HBM)-I values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) - description, derivation and discussion.
;mann M Abstract In 2016, the German Human Biomonitoring Commission (HBM-C) published a statement on its decision to develop HBM-I values for Perfluorooctanoic acid (PFOA) and Perfluorooctanesulfonic acid (PFOS)*. The HBM-I value corresponds to the concentration of a substance in a human biological material below which no adverse health effects are expected, according to current knowledge and assessment by the HBM-C, and, consequently, there is no need for action. Evidence for associations between PFOA- and PFOS-body burden and health outcomes was found for fertility and pregnancy, weights of newborns at birth, li...
Source: Regulatory Toxicology and Pharmacology : RTP - January 11, 2021 Category: Toxicology Authors: Hölzer J, Lilienthal H, Schümann M Tags: Regul Toxicol Pharmacol Source Type: research

Skin Immune Cell Characterization in Juvenile and Adult G öttingen Minipigs.
The objective of our work was first to characterize the main skin immune populations (Langerhans cells, dermal dendritic cells, macrophages and T lymphocytes) in Göttingen Minipigs. In parallel, we compared the skin immune populations from healthy and immunocompromised piglets following oral treatment with cyclosporin A (CsA) at 10 mg/kg/day. We also explored other pathological conditions using a contact dermatitis model in minipigs challenged with a sensitizer, 2,4-dinitrochlorobenzene (DNCB). Langerhans cells and dermal MHCIIlowCD163+ cells were increased one month after oral treatment with CsA at 10 mg/kg/day. The ...
Source: Regulatory Toxicology and Pharmacology : RTP - January 5, 2021 Category: Toxicology Authors: Allais L, Brisebard E, Ravas N, Briffaux JP, Pallardy M Tags: Regul Toxicol Pharmacol Source Type: research

Estimation of toluene exposure in air from bma (s-benzylmercapturic acid) urinary measures using a reverse dosimetry approach based on physiologically pharmacokinetic modeling.
This study aimed to use a reverse dosimetry PBPK modeling approach to estimate toluene atmospheric exposure from urinary measurements of S-benzylmercapturic acid (BMA) in a small group of individuals and to evaluate the uncertainty associated to urinary spot-sampling compared to 24-hour collected urine samples. Each exposure assessment technique was developed namely to estimate toluene air exposure from BMA measurements in 24-hour urine samples (24-h-BMA) and from distributions of daily urinary BMA spot measurements (DUBSM). Model physiological parameters were described based upon age, weight, size and sex. Monte Carlo sim...
Source: Regulatory Toxicology and Pharmacology : RTP - January 3, 2021 Category: Toxicology Authors: Tohon H, Valcke M, Aranda-Rodriguez R, Nong A, Haddad S Tags: Regul Toxicol Pharmacol Source Type: research

Assessment of the Biochemical Pathways for Acetaminophen Toxicity: Implications for its Carcinogenic Hazard Potential.
Abstract In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular ef...
Source: Regulatory Toxicology and Pharmacology : RTP - December 31, 2020 Category: Toxicology Authors: Jaeschke H, Murray FJ, Monnot AD, Jacobson-Kram D, Cohen SM, Hardisty JF, Atillasoy E, Hermanowski-Vosatka A, Kuffner E, Wikoff D, Chappell GA, Bandara SB, Deore M, Pitchaiyan SK, Eichenbaum G Tags: Regul Toxicol Pharmacol Source Type: research

Evaluation of the carcinogenicity of dichloromethane in rats, mice, hamsters and humans.
Abstract Dichloromethane (DCM) is a high production volume chemical (>1000 t/a) mainly used as an industrial solvent. Carcinogenicity studies in rats, mice and hamsters have demonstrated a malignant tumor inducing potential of DCM only in the mouse (lung and liver) at 1000 - 4000 ppm whereas human data do not support a conclusion of cancer risk. Based on this, DCM has been classified as a cat. 2 carcinogen. Dose-dependent toxicokinetics of DCM suggest that DCM is a threshold carcinogen in mice, initiating carcinogenicity via the low affinity/high capacity GSTT1 pathway; a biotransformation pathway that becomes ...
Source: Regulatory Toxicology and Pharmacology : RTP - December 30, 2020 Category: Toxicology Authors: Dekant W, Jean P, Arts J Tags: Regul Toxicol Pharmacol Source Type: research

The Use of Emerging Safety Biomarkers in Nonclinical and Clinical Safety Assessment - the Current and Future State: An IQ DruSafe Industry Survey.
The objectives were to: (1) determine current ESB use in nonclinical and clinical drug development and impact on asset advancement; (2) identify opportunities, gaps, and challenges to greater ESB implementation; and (3) benchmark perspectives on regulatory acceptance. Although ESBs were employed in only 5-50% of studies/programs, most companies used ESBs to some extent, with larger companies demonstrating greater nonclinical use. Inclusion of ESBs in investigational new drug applications (INDs) was similar across all companies; however, differences in clinical trial usage could vary among the prevailing health authority (H...
Source: Regulatory Toxicology and Pharmacology : RTP - December 30, 2020 Category: Toxicology Authors: Zabka TS, Burkhardt J, Reagan WJ, Gautier JC, Glaab WE, Guffroy M, Harding J, Brees D, McDuffie E, Ramaiah L, Schultze AE, Smith JD, Wolfreys A, Dalmas DA Tags: Regul Toxicol Pharmacol Source Type: research

Comparative In Vitro Metabolism of Purified Mogrosides Derived from Monk Fruit Extracts.
The objective of this study was to demonstrate whether individual mogrosides, are metabolized to a common and terminal deglycosylated metabolite, mogrol. An in vitro assay was conducted with pooled human male and female intestinal fecal homogenates (HFH) using mogrosides IIIe, mogroside V, siamenoside I, and isomogroside V at two concentrations over a 48 hour period. The results show that various mogrosides that differ in the linkages and number of glucose units attached to a common cucurbitane backbone, share a common metabolic fate, and are metabolized within 24 hours to mogrol. Aside from an apparent difference in the i...
Source: Regulatory Toxicology and Pharmacology : RTP - December 30, 2020 Category: Toxicology Authors: Bhusari S, Rodriguez C, Tarka SM, Kwok D, Pugh G, Gujral J, Tonucci D Tags: Regul Toxicol Pharmacol Source Type: research

Testing the Validity of a Proposed Dermal Cancer Slope Factor for Benzo[a]pyrene.
Abstract In 2014, the United States Environmental Protection Agency (EPA) proposed a Dermal Slope Factor (DSF) for benzo[a]pyrene (BaP) of 0.006 (μg/day)-1 (USEPA 2014a). It would make cancer risk estimates associated with soil contact 100 times greater than those from soil ingestion and would predict that a large fraction of skin Basal Cell Carcinomas (BCCs) and Squamous Cell Carcinomas (SCCs) worldwide are caused by low level dermal exposures to PAHs, such as BaP. This is not logical given that sunlight (ultraviolet radiation (UV)) exposure is the generally recognized cause of BCCs and SCCs. This paper critic...
Source: Regulatory Toxicology and Pharmacology : RTP - December 24, 2020 Category: Toxicology Authors: Magee BH, Forsberg ND Tags: Regul Toxicol Pharmacol Source Type: research

Incorporating Lines of Evidence from New Approach Methodologies (NAMs) to Reduce Uncertainties in a Category Based Read-Across: A Case Study for Repeated Dose Toxicity.
Abstract A group of triazole compounds was selected to investigate the confidence that may be associated with read-across of a complex data gap: repeated dose toxicity. The read-across was evaluated using Assessment Elements (AEs) from the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF), alongside appraisal of associated uncertainties. Following an initial read-across based on chemical structure and properties, uncertainties were reduced by the integration of data streams such as those from New Approach Methodologies (NAM) and other existing data. In addition, addressing the findings o...
Source: Regulatory Toxicology and Pharmacology : RTP - December 21, 2020 Category: Toxicology Authors: Pestana CB, Firman JW, Cronin MTD Tags: Regul Toxicol Pharmacol Source Type: research

A 13-week subchronic toxicity study of a Dioscorea Rhizome water extract in rats.
This study investigated the potential subchronic toxicity of a D. Rhizome water extract (DRWE) after repeated oral administration at 0, 800, 2000, and 5000 mg/kg/day in rats for 13 weeks. During the study period, clinical signs, mortality, body weight, food consumption, water consumption, urinalysis, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. The 13-week repeated oral administration of DRWE to rats resulted in an increased incidence of zona glomerulosa hypertrophy and hyperplasia in the adrenal gland at dose levels of ≥2000 mg/kg/day in bot...
Source: Regulatory Toxicology and Pharmacology : RTP - December 21, 2020 Category: Toxicology Authors: Cha SB, Kim HS, Bae JS, Song SW, Lim JO, Kim JC Tags: Regul Toxicol Pharmacol Source Type: research

Non-Dioxin-Like Polychlorinated Biphenyl Neurotoxic Equivalents Found in Environmental and Human Samples.
Abstract Non-dioxin like polychlorinated biphenyls (NDL PCB) are recognized neurotoxicants with implications on altered neurodevelopment and neurodegeneration in exposed organisms. Two NDL PCB neurotoxic relative potency schemes have been developed for a single mechanism, namely activity toward the ryanodine receptor (RyR), or combined mechanisms including, but not limited to, alterations of RyR and dopaminergic pathways. We compared the applicability of the two neurotoxic equivalency (NEQ) schemes and applied each scheme to PCB mixtures found in environmental and human serum samples. A multiple mechanistic NEQ pr...
Source: Regulatory Toxicology and Pharmacology : RTP - December 17, 2020 Category: Toxicology Authors: Holland EB, Pessah IN Tags: Regul Toxicol Pharmacol Source Type: research

A cross-industry collaboration to assess if acute oral toxicity (Q)SAR models are fit-for-purpose for GHS classification and labelling.
This study assesses whether currently available acute oral toxicity (AOT) in silico models, provided by the widely employed Leadscope software, are fit-for-purpose for categorization and labelling of chemicals. As part of this study, a large data set of proprietary and marketed compounds from multiple companies (pharmaceutical, plant protection products, and other chemical industries) was assembled to assess the models' performance. The absolute percentage of correct or more conservative predictions, based on a comparison of experimental and predicted GHS categories, was approximately 95%, after excluding a small percentag...
Source: Regulatory Toxicology and Pharmacology : RTP - December 16, 2020 Category: Toxicology Authors: Bercu J, Masuda-Herrera MJ, Trejo-Martin A, Hasselgren C, Lord J, Graham J, Schmitz M, Milchak L, Owens C, Lal SH, Robinson RM, Whalley S, Bellion P, Vuorinen A, Gromek K, Hawkins WA, Van de Gevel I, Vriens K, Kemper R, Naven R, Ferrer P, Myatt GJ Tags: Regul Toxicol Pharmacol Source Type: research

Evidence-based regulations for bioinformatic prediction of allergen cross-reactivity are needed.
Abstract The bioinformatic criteria adopted by regulatory agencies to predict the potential cross reactivity between newly expressed proteins in genetically engineered crops and known allergens involves amino acid identity thresholds and was formulated nearly two decades ago based on the opinion of allergy experts. Over the subsequent years, empirical evidence has been developed indicating that better bioinformatic tools based on amino acid similarity are available to detect real allergen cross-reactive risk while substantially reducing false-positive detections. Although the formulation of safety regulations, in ...
Source: Regulatory Toxicology and Pharmacology : RTP - December 14, 2020 Category: Toxicology Authors: Herman RA, Song P, Mirsky HP, Roper JM Tags: Regul Toxicol Pharmacol Source Type: research

Reproductive and developmental toxicity screening study of an acetone extract of rosemary.
Abstract In 2017, JECFA requested reproductive and developmental toxicity studies to finalize an acceptable daily intake for solvent rosemary extracts. Thus, an OECD 421 reproductive/developmental toxicity study was conducted using an acetone rosemary extract that complied with JECFA and EFSA food additive specifications. Rosemary extract was provided to rats at dietary concentrations of 0 (control), 2100, 3600, or 5000 mg/kg, for 14 days before mating, during mating, and thereafter (throughout gestation and up to Lactation Day 13 for females) until necropsy. General toxicity (clinical signs, body weight, food con...
Source: Regulatory Toxicology and Pharmacology : RTP - December 12, 2020 Category: Toxicology Authors: Phipps KR, Danielewska-Nikiel B, Mushonganono J, Baldwin N Tags: Regul Toxicol Pharmacol Source Type: research

Risk Assessment of Predicted Serum Concentrations of Bisphenol A in Children and Adults Following Treatment with Dental Composite Restoratives, Dental Sealants, or Orthodontic Adhesives using Physiologically Based Pharmacokinetic Modeling.
Abstract Bisphenol A (BPA) is a chemical used to manufacture bisphenol A glycidyl methacrylate (BisGMA). BisGMA has been used for decades in dental composite restoratives, sealants, and adhesives. Based on published studies, exposure to low concentrations of BPA are possible from dental and orthodontic devices. The serum BPA concentrations arising from such devices and oral doses were predicted using a PBPK model in children and adult females based on 1) published extraction data for cured and uncured 3M ESPE Filtek Supreme Ultra Flowable, 3M ESPE Filtek Bulk Fill Restorative, and 3M ESPE Clinpro Sealant and 2) pu...
Source: Regulatory Toxicology and Pharmacology : RTP - December 7, 2020 Category: Toxicology Authors: Bagley BD, Smith JN, Teeguarden JG Tags: Regul Toxicol Pharmacol Source Type: research

A weight of evidence assessment of the genotoxicity of 2,6-xylidine based on existing and new data, with relevance to safety of lidocaine exposure.
Abstract Lidocaine has not been associated with cancer in humans despite 8 decades of therapeutic use. Its metabolite, 2,6-xylidine, is a rat carcinogen, believed to induce genotoxicity via N-hydroxylation and DNA adduct formation, a non-threshold mechanism of action. To better understand this dichotomy, we review literature pertaining to metabolic activation and genotoxicity of 2,6-xylidine, identifying that it appears resistant to N-hydroxylation and instead metabolises almost exclusively to DMAP (an aminophenol). At high exposures (sufficient to saturate phase 2 metabolism), this may undergo metabolic threshold...
Source: Regulatory Toxicology and Pharmacology : RTP - December 7, 2020 Category: Toxicology Authors: Kirkland DJ, Sheil ML, Streicker MA, Johnson GE Tags: Regul Toxicol Pharmacol Source Type: research

Subchronic toxicity study in rats evaluating herbicide-tolerant soybean DAS-68416-4.
Abstract A subchronic toxicity study was conducted in Wistar rats to evaluate the potential health effects of genetically modified (GM) herbicide-tolerant soybean DAS-68416-4. Rats were fed with diets containing toasted meal produced from GM soybean engineered with aad-12 and pat genes or containing non-GM soybean at a dose of 30.0, 15.0, or 7.5%,w/w% and 0% (control group) for 90 consecutive days. Animals were evaluated for general behavior, body weight gain, food consumption, food use efficiency, etc. At the middle and end of the study, blood and serum samples were collected for routine and biochemical assays. I...
Source: Regulatory Toxicology and Pharmacology : RTP - November 28, 2020 Category: Toxicology Authors: Zhang L, Li SF, Zhou QH, Liu YH, Zhang J, Qian ZY Tags: Regul Toxicol Pharmacol Source Type: research

A call for action on the development and implementation of new methodologies for safety assessment of chemical-based products in the EU - A short communication.
Abstract Safety assessment of chemicals and products in the European Union (EU) is based on decades of practice using primarily animal toxicity studies to model hazardous effects in humans. Nevertheless, there has been a long-standing ethical concern about using experimental animals. In addition, animal models may fail to predict adverse effects in humans. This has provided a strong motivation to develop and use new approach methodologies and other alternative sources of evidence. A key challenge for this is integration of evidence from different sources. This paper is a call for action with regard to development,...
Source: Regulatory Toxicology and Pharmacology : RTP - November 26, 2020 Category: Toxicology Authors: Knight DJ, Deluyker H, Chaudhry Q, Vidal JM, de Boer A Tags: Regul Toxicol Pharmacol Source Type: research

A review to support the derivation of a worst-case dermal penetration value for nanoparticles.
Abstract Data on dermal penetration of nanoparticles (NPs) was reviewed with the goal to establish a worst-case dermal penetration value for NPs. To this aim, the main focus was on studies providing quantitative dermal penetration data (29 studies). In vivo dermal penetration studies and ex vivo studies based on skin explants were included. These studies used NPs with different compositions, dimensions, and shapes. The overall results showed that skin is an efficient barrier for NPs, indistinctly of their properties. However, some studies reported that a small percentage of the applied NP dose penetrated the skin ...
Source: Regulatory Toxicology and Pharmacology : RTP - November 26, 2020 Category: Toxicology Authors: Gimeno-Benito I, Giusti A, Dekkers S, Haase A, Janer G Tags: Regul Toxicol Pharmacol Source Type: research

Simple methodology for ensuring the precision of measuring radioactivity at low concentrations in very small tissues using quantitative whole-body autoradiography.
Abstract Quantitative whole-body autoradiography (QWBA) is largely used to evaluate tissue distribution of small molecule drugs. In QWBA, radioactivity is measured as the intensity obtained from the autoradiogram. It is known that lower intensity per a region of interest (ROI) or smaller size of ROI increases the variability of intensity. In fact, as some tissues are very small (e.g., choroidea), ensuring reliability on the intensity for measuring radioactivity in these tissues is difficult in case of under- or over-estimation of radioactivity concentration owing to their variation of low radioactivity intensity o...
Source: Regulatory Toxicology and Pharmacology : RTP - November 20, 2020 Category: Toxicology Authors: Hironaka T, Inazawa K, Tanaka Y, Hasegawa H Tags: Regul Toxicol Pharmacol Source Type: research

Evaluating chemical similarity as a measure to identify potential substances of very high concern.
Abstract Due to the large amount of chemical substances on the market, fast and reproducible screening is essential to prioritize chemicals for further evaluation according to highest concern. We here evaluate the performance of structural similarity models that are developed to identify potential substances of very high concern (SVHC) based on structural similarity to known SVHCs. These models were developed following a systematic analysis of the performance of 112 different similarity measures for varying SVHC-subgroups. The final models consist of the best combinations of fingerprint, similarity coefficient and...
Source: Regulatory Toxicology and Pharmacology : RTP - November 20, 2020 Category: Toxicology Authors: Wassenaar PNH, Rorije E, Vijver MG, Peijnenburg WJGM Tags: Regul Toxicol Pharmacol Source Type: research

Antimony release from polyester textiles by artificial sweat solutions: A call for a standardized procedure.
Abstract Polyester fibers are usually contaminated by antimony because of its use as a catalyst in the production of polyethylene terephthalate and as a flame retardant synergist in a variety of new and recycled polymers. The present study determined the release of antimony (at total concentrations ranging from about 125 to 470 μg g-1) from polyester textile samples designed to be in contact with human skin using standard artificial sweat solutions (ISO 105-E04 and European Commission, 2014). The study also examined the role of different experimental parameters on the release of the metalloid. Overall, and ...
Source: Regulatory Toxicology and Pharmacology : RTP - November 19, 2020 Category: Toxicology Authors: Biver M, Turner A, Filella M Tags: Regul Toxicol Pharmacol Source Type: research

Genotoxicity and subchronic toxicity studies of supercritical carbon dioxide and acetone extracts of rosemary.
Abstract Toxicology studies conducted with oil-soluble rosemary extracts to support authorization as a food additive (antioxidant) in the EU include an Ames test using a supercritical carbon dioxide extract (D74), a full 90-day study using D74 and an acetone extract (F62), and an investigative 90-day study with a 28-day recovery period (using D74 only). D74 was non-mutagenic in the Ames test. In the full 90-day study, where rats (20/sex/group) were either provided control diet or diets containing D74 (300, 600, or 2400 mg/kg) or F62 (3800 mg/kg), liver enlargement and hepatocellular hypertrophy were observed. ...
Source: Regulatory Toxicology and Pharmacology : RTP - November 19, 2020 Category: Toxicology Authors: Phipps KR, Lozon D, Baldwin N Tags: Regul Toxicol Pharmacol Source Type: research

Aloe gel-base food products: Chemical, toxicological, and regulatory aspects.
Abstract Aloe products are increasingly valued as ingredients in food supplements and flavoring agents. In early March 2020, the European Commission drafted a ban on the use of Aloe products that contain hydroxyanthracene derivatives (HADs) in food, following the opinion on concerns about the toxicity of vegetable extracts containing HADs carried out by the European Food Safety Authority (EFSA). Aloe gel preparation is characterized by minimal amounts of HADs, only present as contaminants during extraction, compared to other sold Aloe preparations such as Aloe latex and Aloe whole leaf extract. This review provide...
Source: Regulatory Toxicology and Pharmacology : RTP - November 19, 2020 Category: Toxicology Authors: Baldi A, Sommella E, Campiglia P, Daglia M Tags: Regul Toxicol Pharmacol Source Type: research

Industry experiences with immune-mediated findings in biotherapeutic nonclinical toxicology studies.
Abstract With the growth of monoclonal antibodies and other proteins as major modalities in the pharmaceutical industry, there has been an increase in pharmacology and toxicity testing of biotherapeutics in animals. Animals frequently mount an immune response to human therapeutic proteins. This can result in asymptomatic anti-drug antibody formation, immune complexes that affect drug disposition and/or organ function such as kidney, cytokine release responses, fatal hypersensitivity, or a range of reactions in between. In addition, an increasing number of oncology therapeutics are being developed that enhance or d...
Source: Regulatory Toxicology and Pharmacology : RTP - November 18, 2020 Category: Toxicology Authors: MacLachlan TK, Kronenberg S, Marshall N, Andrews L, Berens SJ, Brouta F, Fogal B, Freebern W, Herzyk D, Kamperschroer C, Kiessling A, Schneidkraut M, Maier C Tags: Regul Toxicol Pharmacol Source Type: research

Safety assessment of ethanolic root extract of Zaleya decandra (EEZD) in Wistar rats.
Abstract Zaleya decandra is a prostrate, glabrous, succulent herb of the family Aizoaceae. In recent years the pharmacological efficacy of the plant such as the hepatoprotective, antimicrobial, antidiabetic, anti-inflammatory and anticancer activities has been reported. However, a long-term toxicity study of Z. decandra is yet to be carried out. In the present study, the acute dose of 2000 mg/kg b.w. of ethanolic extract of Z. decandra (EEZD) administered orally to Wistar rats gained gradual weight with time and appeared healthy without any record of mortality. In the sub-chronic toxicity study, the rats showed ...
Source: Regulatory Toxicology and Pharmacology : RTP - November 17, 2020 Category: Toxicology Authors: Deivasigamani M, Kannan N, Sekar N, Lakshmanan H Tags: Regul Toxicol Pharmacol Source Type: research

Pharmacokinetics and efficacy of atropine sulfate/obidoxime chloride Co-formulation against VX in a Guinea pig model.
In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation. PMID: 33212192 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - November 16, 2020 Category: Toxicology Authors: Kentrop J, Savransky V, Klaassen SD, van Groningen T, Bohnert S, Cornelissen AS, Cochrane L, Barry J, Joosen MJA Tags: Regul Toxicol Pharmacol Source Type: research

A 90-day drinking water study in mice to characterize early events in the cancer mode of action of 1,4-dioxane.
Abstract Studies demonstrate that with sufficient dose and duration, 1,4-dioxane (1,4-DX) induces liver tumors in laboratory rodent models. The available evidence aligns with a threshold-dependent, tumor promotion mode of action (MOA). The MOA and key events (KE) in rats are well developed but less so in the mouse. Therefore, we conducted a 90-day drinking water study in female mice to evaluate early KE at 7, 28, and 90 days. Female B6D2F1/Crl mice consumed drinking water containing 0, 40, 200, 600, 2000 or 6000 ppm. 1,4-DX was detected in blood at 90-days of exposure to 6000 ppm, but not in the other exposure...
Source: Regulatory Toxicology and Pharmacology : RTP - November 12, 2020 Category: Toxicology Authors: Lafranconi M, Budinsky R, Corey L, Klapacz J, Crissman J, LeBaron M, Golden R, Pleus R Tags: Regul Toxicol Pharmacol Source Type: research

The activity of methacrylate esters in skin sensitisation test methods II. A review of complementary and additional analyses.
Abstract Allergic contact dermatitis is an important occupational health issue, and there is a need to identify accurately those chemicals that have the potential to induce skin sensitisation. Hazard identification was performed initially using animal (guinea pig and mouse) models. More recently, as a result of the drive towards non-animal methods, alternative in vitro and in silico approaches have been developed. Some of these new in vitro methods have been formally validated and have been assigned OECD Test Guideline status. The performance of some of these recently developed in vitro methods, and of 2 quantitat...
Source: Regulatory Toxicology and Pharmacology : RTP - November 10, 2020 Category: Toxicology Authors: Kimber I Tags: Regul Toxicol Pharmacol Source Type: research

Evaluation of dietary dose administration as an alternative to oral gavage in the rodent uterotrophic and Hershberger assays.
In this study, equivalent doses of positive control chemicals administered via dietary and gavage routes of administration were compared in the uterotrophic (17α-ethinyl estradiol) and Hershberger (flutamide, linuron, dichloro-2,2-bis(4-chlorophenyl) ethane; 4,4'-DDE) assays in ovariectomized and castrated rats, respectively. For all positive control chemicals tested, statistically significant changes in organ weights and decreases in food consumption were observed by both routes of test substance administration. Decreased body weight gain observed for dietary linuron and 4,4'-DDE indicates that the maximum tolerated...
Source: Regulatory Toxicology and Pharmacology : RTP - November 9, 2020 Category: Toxicology Authors: Markell L, O'Connor JC, Luo R, Klems J, Sayers B, Mingoia R Tags: Regul Toxicol Pharmacol Source Type: research

Assessment of the potential allergenicity and toxicity of Pichia proteins in a novel leghemoglobin preparation.
In conclusion, LegH Prep from this P. pastoris production process is unlikely to pose a risk of food allergenicity. PMID: 33171209 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - November 7, 2020 Category: Toxicology Authors: Reyes TF, Chen Y, Fraser RZ, Chan T, Li X Tags: Regul Toxicol Pharmacol Source Type: research

The performance, reliability and potential application of in silico models for predicting the acute oral toxicity of pharmaceutical compounds.
Abstract Acute oral toxicity (AOT) information is utilized to categorize compounds according to the severity of their hazard and used to inform risk assessments for human health and the environment. Given the wealth of historical AOT information and technological advances, in silico models are being created and evaluated as potential tools to predict the AOT of compounds and reduce reliance on animal testing. Utilizing a historical database of AOT data on 371 Bristol Myers Squibb pharmaceutical compounds (PCs) (195 pharmaceutical intermediates and 176 active pharmaceutical ingredients), we evaluated two pioneering...
Source: Regulatory Toxicology and Pharmacology : RTP - November 6, 2020 Category: Toxicology Authors: Graham J, Rodas M, Hillegass J, Schulze G Tags: Regul Toxicol Pharmacol Source Type: research

Computational identification of preservatives with potential neuronal cytotoxicity.
In this study, we developed a Quantitative Structure-Activity Relationships (QSAR) model for the identification of potential neurotoxicants. A set of 681 chemicals was utilized to construct a robust prediction model using oversampling and Random Forest algorithms. Within a defined applicability domain, the independent test on 452 chemicals showed a high accuracy of 87.7%. The application of the model to 157 preservatives identified 15 chemicals potentially toxic to neuronal cells. Three of them were further validated by in vitro experiments. The results suggested that further experiments are desirable for assessing the neu...
Source: Regulatory Toxicology and Pharmacology : RTP - November 4, 2020 Category: Toxicology Authors: Kan HL, Wang CC, Lin YC, Tung CW Tags: Regul Toxicol Pharmacol Source Type: research

Corrigendum to "28-day somatic gene mutation study of 1-Bromopropane in female big blue ® B6C3F1 Mice via whole-Body inhalation: Support for a carcinogenic threshold" [Regul. Toxicol. Pharmacol., 104 (2019) 1-7].
Corrigendum to "28-day somatic gene mutation study of 1-Bromopropane in female big blue® B6C3F1 Mice via whole-Body inhalation: Support for a carcinogenic threshold" [Regul. Toxicol. Pharmacol., 104 (2019) 1-7]. Regul Toxicol Pharmacol. 2020 Nov 03;:104814 Authors: Stelljes M, Young R, Weinberg J PMID: 33158580 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - November 3, 2020 Category: Toxicology Authors: Stelljes M, Young R, Weinberg J Tags: Regul Toxicol Pharmacol Source Type: research

Considerations for setting occupational exposure limits for novel pharmaceutical modalities.
Abstract In order to develop new and effective medicines, pharmaceutical companies must be modality agnostic. As science reveals an enhanced understanding of biological processes, new therapeutic modalities are becoming important in developing breakthrough therapies to treat both rare and common diseases. As these new modalities progress, concern and uncertainty arise regarding their safe handling by the researchers developing them, employees manufacturing them and nurses administering them. This manuscript reviews the available literature for emerging modalities (including oligonucleotides, monoclonal antibodies,...
Source: Regulatory Toxicology and Pharmacology : RTP - October 31, 2020 Category: Toxicology Authors: Graham J, Hillegass J, Schulze G Tags: Regul Toxicol Pharmacol Source Type: research

Statistical analysis of in vivo alkaline comet assay data - Comparison of median and geometric mean as centrality measures.
Abstract The comet assay is one of the standard tests to evaluate the genotoxic potential of a test item and able to detect DNA strand breaks in cells or isolated nuclei from various tissues. The in vivo alkaline comet assay is part of the standard test battery, given in option 2 (ICH S2 (R1), 2012) and a follow-up test in the EFSA framework on genotoxicity testing.The current OECD guideline for the testing of chemicals No. 489 directly affects the statistical analysis of comet data as it suggests using the median per slide and the mean of all medians per animal. However, alternative approaches can be used if scie...
Source: Regulatory Toxicology and Pharmacology : RTP - October 27, 2020 Category: Toxicology Authors: Tug T, Ickstadt K, Kunz M, Sutter A, Igl BW Tags: Regul Toxicol Pharmacol Source Type: research

Choosing the best for preventing the worst: A structured analysis of the selection of risk management options in REACH restriction dossiers.
Abstract Under the European chemicals legislation REACH (Registration, Evaluation, Authorisation and restriction of CHemicals), the use of chemicals posing an unacceptable risk for humans and the environment can be restricted. This requires that regulatory authorities of EU member states, or the European Chemicals Agency on request of the Commission, submit a restriction proposal in which they suggest one or multiple risk management options (RMOs). The options are recommended to be evaluated in a socio-economic analysis (SEA) using defined criteria. This paper explores the drivers of the selection of the preferred...
Source: Regulatory Toxicology and Pharmacology : RTP - October 26, 2020 Category: Toxicology Authors: Hilber I, Gabbert S Tags: Regul Toxicol Pharmacol Source Type: research

Safety evaluation of Eucommia ulmoides extract.
Abstract Eucommia ulmoides Oliver is native to China and frequently used in traditional Chinese medicine formulations. However, studies show that Eucommia ulmoides extract (EUE) are potentially genotoxic and nephrotoxic. To evaluate its safety, the Ames test, bone marrow micronucleus assay and chromosomal aberration assay, along with acute (24 h) and sub-chronic (13 weeks) toxicity were conducted. EUE was non-genotoxic within the dose ranges of 0.0352-22 mg/plate (raw plant equivalent as below), 22-88 g/kg body weight and 2-20 mg/mL. The maximum tolerated dose of EUE was not less than 168 g/kg,...
Source: Regulatory Toxicology and Pharmacology : RTP - October 26, 2020 Category: Toxicology Authors: Luo X, Wu J, Li Z, Jin W, Zhang F, Sun H, Shi Y Tags: Regul Toxicol Pharmacol Source Type: research

Thirteen-week oral toxicity study of fermented ginseng, GBCK25, in Sprague-Dawley rats.
In conclusion, there were no toxicological changes upon repeated oral gavage of GBCK25 at doses of 250, 500, or 1000 mg/kg/day in Sprague-Dawley rats over 13 weeks. The no-observed-adverse-effect level of GBCK25 was 1000 mg/kg/day in both sexes of Sprague-Dawley rat. PMID: 33122046 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - October 26, 2020 Category: Toxicology Authors: Kim KT, Cho DW, Yang MJ, Kim DH, Shin SH, Hwang JH, Woo DH, Shin DG, Seo JH, Yang YS, Han SC Tags: Regul Toxicol Pharmacol Source Type: research

The translational value of animal models in orphan medicines designations for rare paediatric neurological diseases.
Abstract Rare diseases are characterized by a substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Appropriate animal models, based on the knowledge of the molecular pathology of the human disease, are a significant element to support the medical plausibility of an orphan designation during the development of orphan medicines for rare neurological diseases. This observational, retrospective study aims to investigate the clinical or nonclinical nature of data submitted to support medical plausibility of orphan designations in the EU (2001-...
Source: Regulatory Toxicology and Pharmacology : RTP - October 26, 2020 Category: Toxicology Authors: Duarte DM, Beatriz da Silva Lima M, Sepodes B Tags: Regul Toxicol Pharmacol Source Type: research

Rebuttal to the letters to the editors by Terry et al. and Sewell et al. regarding Heringa et al. (2020).
PMID: 33091463 [PubMed - as supplied by publisher] (Source: Regulatory Toxicology and Pharmacology : RTP)
Source: Regulatory Toxicology and Pharmacology : RTP - October 19, 2020 Category: Toxicology Authors: Heringa MB, Cnubben NHP, Slob W, Pronk MEJ, Muller A, Woutersen M, Hakkert BC Tags: Regul Toxicol Pharmacol Source Type: research

Updating exposure assessment for skin sensitization quantitative risk assessment for fragrance materials.
Abstract In 2008, a proposal for assessing the risk of induction of skin sensitization to fragrance materials Quantitative Risk Assessment 1 (QRA1) was published. This was implemented for setting maximum limits for fragrance materials in consumer products. However, there was no formal validation or empirical verification after implementation. Additionally, concerns remained that QRA1 did not incorporate aggregate exposure from multiple product use and included assumptions, e.g. safety assessment factors (SAFs), that had not been critically reviewed. Accordingly, a review was undertaken, including detailed re-evalu...
Source: Regulatory Toxicology and Pharmacology : RTP - October 16, 2020 Category: Toxicology Authors: Api AM, Basketter D, Bridges J, Cadby P, Ellis G, Gilmour N, Greim H, Griem P, Kern P, Khaiat A, O'Brien J, Rustemeyer T, Ryan C, Safford B, Smith B, Vey M, White IR Tags: Regul Toxicol Pharmacol Source Type: research

Management of pharmaceutical ICH M7 (Q)SAR predictions - The impact of model updates.
Abstract Pharmaceutical applicants conduct (Q)SAR assessments on identified and theoretical impurities to predict their mutagenic potential. Two complementary models-one rule-based and one statistical-based-are used, followed by expert review. (Q)SAR models are continuously updated to improve predictions, with new versions typically released on a yearly basis. Numerous releases of (Q)SAR models will occur during the typical 6-7 years of drug development until new drug registration. Therefore, it is important to understand the impact of model updates on impurity mutagenicity predictions over time. Compounds represe...
Source: Regulatory Toxicology and Pharmacology : RTP - October 12, 2020 Category: Toxicology Authors: Hasselgren C, Bercu J, Cayley A, Cross K, Glowienke S, Kruhlak N, Muster W, Nicolette J, Reddy MV, Saiakhov R, Dobo K Tags: Regul Toxicol Pharmacol Source Type: research

Assessment of veterinary drug residues in food: Considerations when dealing with sub-optimal data.
Abstract The use of veterinary drugs in food-producing animals may lead to residues in animal-derived foodstuffs, potentially posing a risk to human safety. While the process of veterinary drug residue risk assessment continues to evolve as new data emerges, a recurring challenge is when sub-optimal or incomplete data are provided with the expectation of supporting a robust risk assessment. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is comprised of international experts who routinely deal with such data challenges when performing veterinary drug residue evaluations. Recent developments in veterin...
Source: Regulatory Toxicology and Pharmacology : RTP - October 12, 2020 Category: Toxicology Authors: Chicoine A, Erdely H, Fattori V, Finnah A, Fletcher S, Lipp M, Sanders P, Scheid S Tags: Regul Toxicol Pharmacol Source Type: research

A review of clinical pharmacology deficiencies of European centralised drug marketing authorisation applications.
Abstract The aim of this observational review was to review trends in deficiencies in clinical pharmacology dossiers by analysing the frequency and characteristics of major objections (MOs) related to clinical pharmacokinetics and dose-exposure-response (DER) relationships in assessment reports for medicinal products submitted in centralised procedures to the European Medicines Agency (EMA). Initial Assessor (Day 120) assessment reports between 2013 and 2018 were reviewed MOs and characterised with regards to ATC code, orphan status, legal basis and type of molecule, major objection topic and if scientific advice ...
Source: Regulatory Toxicology and Pharmacology : RTP - October 10, 2020 Category: Toxicology Authors: Hay JL, O'Sullivan J, Kerwash E, Ilie AR, Cole SM Tags: Regul Toxicol Pharmacol Source Type: research

A critical review of the acetaminophen preclinical carcinogenicity and tumor promotion data and their implications for its carcinogenic hazard potential.
The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophe...
Source: Regulatory Toxicology and Pharmacology : RTP - October 8, 2020 Category: Toxicology Authors: Murray J, Monnot A, Jacobson-Kram D, Cohen SM, Hardisty J, Bandara S, Kovochich M, Deore M, Pitchaiyan S, Gelotte C, Lai JC, Atillasoy E, Hermanowski-Vosatka A, Kuffner E, Unice K, Yang K, Gebremichael Y, Howell BA, Eichenbaum G Tags: Regul Toxicol Pharmacol Source Type: research

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.
Abstract 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 collaborat...
Source: Regulatory Toxicology and Pharmacology : RTP - October 7, 2020 Category: Toxicology Authors: Parris P, Martin EA, Stanard B, Glowienke S, Dolan DG, Li K, Binazon O, Giddings A, Whelan G, Masuda-Herrera M, Bercu J, Broschard T, Bruen U, Callis CM, Stults CLM, Erexson GL, Cruz MT, Nagao LM Tags: Regul Toxicol Pharmacol Source Type: research

Facilitation of risk assessment with evidence-based methods - A framework for use of systematic mapping and systematic reviews in determining hazard, developing toxicity values, and characterizing uncertainty.
Abstract Systematic review tools and approaches developed for clinical medicine are often difficult to apply "off the shelf" in order to meet the needs of chemical risk assessments. To address such, we propose an approach that can be used by practitioners for using evidence-based methods to facilitate the risk assessment process. The framework builds on and combines efforts conducted to date by a number of agencies and researchers; the novelty is in combining these efforts with a practical understanding of risk assessment, and translating such into a 'step-by-step' guide. The approach relies on three key...
Source: Regulatory Toxicology and Pharmacology : RTP - October 7, 2020 Category: Toxicology Authors: Wikoff D, Lewis RJ, Erraguntla N, Franzen A, Foreman J Tags: Regul Toxicol Pharmacol Source Type: research

A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals.
Wolterink G, Woutersen R, Zvonar Z, Heusinkveld H, Braakhuis H Abstract Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative test methods and enhanced understanding of carcinogenic processes, it is believed that tumour formation can now be better predicted using mechanistic information. A workshop organised by the European Pa...
Source: Regulatory Toxicology and Pharmacology : RTP - October 6, 2020 Category: Toxicology Authors: Luijten M, Corvi R, Mehta J, Corvaro M, Delrue N, Felter S, Haas B, Hewitt NJ, Hilton G, Holmes T, Jacobs MN, Jacobs A, Lamplmair F, Lewis D, Madia F, Manou I, Melching-Kollmuss S, Schorsch F, Schutte K, Sewell F, Strupp C, Willem van der Laan J, Wolf DC, Tags: Regul Toxicol Pharmacol Source Type: research

Toxicological risk assessment of bisphenol a released from dialyzers under simulated-use and exaggerated extraction conditions.
Abstract Bisphenol A (BPA) belongs to a group of chemicals used in the production of polycarbonate, polysulfone, and polyethersulfone which are used, among other applications, in the manufacture of dialyzers. While exposure to BPA is widespread in the general population, dialysis patients represent a population with potentially chronic parenteral BPA exposures. To assess the potential risk of BPA exposure to dialysis patients through dialyzer use, exposure estimates were calculated based on BPA levels measured by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry following ext...
Source: Regulatory Toxicology and Pharmacology : RTP - September 30, 2020 Category: Toxicology Authors: Badding MA, Vargas JR, Fortney J, Cheng QJ, Ho CH Tags: Regul Toxicol Pharmacol Source Type: research