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  • Estimation of time to compromised tenability in fires: is it time to change paradigms?
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-15
    Juergen Pauluhn

    The ISO standard 13571 estimates the time to the compromised tenability of people in enclosed fires. This is understood as the time which must be available for the structural design to pass an evacuation, or an escape paradigm for the evacuation of burning buildings. As with all emergency response planning values, such once-in-a-lifetime events cannot readily be validated side-by-side. Consequently, risk assessors must refer to animal-based reference data fitting the scenario of concern closely. The analysis detailed in this paper used the concentration × time (Cxt)-matrix of point of departures (PODs) from rats acutely exposed to carbon monoxide (CO), which is amongst the most abundant toxic fire gases. The objective of the analysis was to clarify whether the time- and effect-adjusted nonlethal threshold concentration LCt01 × 1/3 from acute rat inhalation studies is suited to model thresholds characterizing any ‘impairment of escape’ in humans. Modeled outcomes are compared with published reference data from human volunteers exposed at the similar C × t's of CO at 800 ppm × 1-h and 100 ppm × 8-h. These exposure durations match the maximum escape duration of 1-h considered in the ISO standard 13571 and standards enforcing occupational exposure limits of 8-h duration. The reference PODs indicative of ‘impairment of escape’ in healthy adults relied on C × t's below those eliciting any loss of motor function or psychoneurological functions. The comparison of the LCt01 × 1/3 based modeled outcomes from rats match favorably with the effect-based PODs from humans. Consistent with published evidence from humans, carboxyhemoglobin (COHb) saturation—a biomarker of exposure rather than of effect—failed to reliably predict effect-based outcomes. Unlike the LCt01 × 1/3 threshold approach, the COHb-based median approach used by ISO TS 13571 is inconsistent with human evidence and both over- and under-estimates the CO-related potency for causing incapacitation at non-toxic and critically-toxic C × ‘s, respectively. In summary, it seems timely that the ISO TS 13571 standard pays attention to scientific progress in relevant toxicity information and refinements to scientific methods shown to adequately predict human risks.

    更新日期:2020-01-15
  • A review of the evidence to support interim reference level for dietary lead exposure in adults
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-13
    Laurie C. Dolan; Brenna M. Flannery; Dana Hoffman-Pennesi; Alexandra Gavelek; Olivia E. Jones; Richard Kanwal; Beverly Wolpert; Kathleen Gensheimer; Sherri Dennis; Suzanne Fitzpatrick

    FDA developed the interim reference level (IRL) for lead of 3 μg/day in children and 12.5 μg/day in women of childbearing age (WOCBA) to better protect the fetus from lead toxicity. These IRLs correspond to a blood lead level (BLL) of 0.5 μg/dL in both populations. The current investigation was performed to determine if the IRL for WOCBA should apply to the general population of adults. A literature review of epidemiological studies was conducted to determine whether a BLL of 0.5 μg/dL is associated with adverse effects in adults. Some studies reported adverse effects over a wide range of BLLs that included 0.5 μg/dL adding uncertainty to conclusions about effects at 0.5 μg/dL; however, no studies clearly identified this BLL as an adverse effect level. Results also showed that the 75 μg/day lead PTTDI for adults may not be health protective, supporting use of a lower reference value for lead toxicity in this population group. Use of the 12.5 μg/day IRL as a benchmark for dietary lead intake is one way FDA will ensure that dietary lead intake in adults is reduced.

    更新日期:2020-01-14
  • A bioinformatics workflow for the evaluation of RT-qPCR primer specificity: Application for the assessment of gene expression data reliability in toxicological studies
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-13
    Bhaja K. Padhi; Guillaume Pelletier; Philip S. Shwed

    The reliability of Reverse Transcription quantitative real-time PCR (RT-qPCR) gene expression data depends on proper primer design and RNA quality controls. Despite freely available genomic databases and bioinformatics tools, primer design deficiencies can be found across life science publications. In order to assess the prevalence of such deficiencies in the toxicological literature, 504 primer sets extracted from a random selection of 70 recent rat toxicological studies were evaluated. The specificity of each primer set was systematically analysed using a bioinformatics workflow developed from publicly available resources (NCBI Primer BLAST, in silico PCR in UCSC genome browser, Ensembl DNA database). Potential mismatches (9%), cross-matches (13.5%), co-amplification of multiple gene splice variants (9%) and sub-optimal amplicon sizes (25%) were identified for a significant proportion of the primer sets assessed in silico. Quality controls for gDNA contamination of RNA samples were infrequently reported in the surveyed manuscripts. Hence, the impacts of gDNA contamination on RT-qPCR data were further investigated, revealing that lowly expressed genes presented higher susceptibility to contaminating gDNA. In addition to the retrospective identification of potential primer design issues presented in this study, the described bioinformatics workflow can also be used prospectively to select candidate primer sets for experimental validation.

    更新日期:2020-01-14
  • Derivation of whole blood biomonitoring equivalents for lithium for the interpretation of biomonitoring data
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-11
    S. Ramoju; M. Andersen; D. Poddalgoda; A. Nong; N. Karyakina; N. Shilnikova; K. Krishnan; D. Krewski

    Introduction Lithium salts have numerous industrial uses and are also used in the treatment of bipolar disorders. The main source of lithium exposure to the general population is drinking water and foods. Lithium is nephrotoxic at higher doses. Thus, oral exposure guidelines for lithium have been derived, including ICH's permitted daily exposure (PDE = 0.008 mg lithium/kg-bw/day) adopted by Health Canada and the United States Environmental Protection Agency's (U.S. EPA) provisional peer reviewed toxicity value (PPRTV = 0.002 mg lithium/kg-bw/day), both based on human data. Objective To derive whole blood biomonitoring equivalents (BEs) associated with PDE and PPRTV to interpret population-level biomonitoring data in health risk context. Method A simple kinetic relationship based on plasma clearance value (0.5 L/kg-bw/day) and the oral absorption fraction (100%) was used to derive blood BEs for PDE and PPRTV. Results and discussion: This analysis resulted in BE values in plasma, and whole blood of 16 and 10 μg/L, respectively, based on the PDE values developed by the Health Canada and of 4.2 and 2.7 μg/L, respectively, based on the PPRTV developed by U.S. EPA. Conclusion The derived BE values can be used to interpret population-level biomonitoring data.

    更新日期:2020-01-13
  • 21st Century Approaches for Evaluating Exposures, biological activity, and risks of complex substances: Workshop highlights
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-11
    Ursula G. Sauer; Robert A. Barter; Richard A. Becker; Emilio Benfenati; Elisabet Berggren; Bruno Hubesch; Heli M. Hollnagel; Kunifumi Inawaka; Athena M. Keene; Philipp Mayer; Kathleen Plotzke; Robert Skoglund; Océane Albert

    The June 2019 workshop 21st Century Approaches for Evaluating Exposures, Biological Activity, and Risks of Complex Substances, co-organised by the International Council of Chemical Association's Long-Range Research Initiative and the European Commission's Joint Research Centre, is summarised. Focus was the need for improved approaches to evaluate the safety of complex substances. Approximately 10% and 20% of substances registered under the EU chemicals legislation are ‘multi-constituent substances’ and ‘substances of unknown or variable compositions, complex reaction products and biological substances’ (UVCBs), respectively, and UVCBs comprise approximately 25% of the U.S. Toxic Substances Control Act Inventory. Workshop participants were asked to consider how the full promise of new approach methodologies (NAMs) could be brought to bear to evaluate complex substances. Sessions focused on using NAMs for screening, biological profiling, and in complex risk evaluations; improving read-across approaches employing new data streams; and methods to evaluate exposure and dosimetry. The workshop concluded with facilitated discussions to explore actionable steps forward. Given the diversity of complex substances, no single ‘correct’ approach was seen as workable. The path forward should focus on ‘learning by doing’ by developing and openly sharing NAM-based fit-for-purpose case examples for evaluating biological activity, exposures and risks of complex substances.

    更新日期:2020-01-13
  • Target-specific micronucleus induction by colon carcinogens: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 1,2-dimethyl-hydrazine
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-11
    Hisako Hori; Satomi Shimoyoshi; Yasuhiro Tanaka; Wataru Fujii; Yoshinori Kitagawa; Makoto Hayashi

    Genotoxicity occurring at the target organs of carcinogenesis is important for understanding the mechanisms of chemical carcinogenicity and also for setting of threshold estimation. In vivo gene mutations have been evaluated by transgenic animal models in which any organ can be targeted; however, the methodologies that have been applied to assess chromosomal aberrations including micronucleus induction, are organ restricted, (often to bone marrow hematopoietic cells, as a common example). For food and food-related chemicals, the digestive tract is the important target organ as it is the organ of first contact. In the present study, we used 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 1,2-dimethylhydrazine (DMH) as model chemicals of carcinogens primarily targeting the colon. We evaluated the applicability of colon cells and hepatocytes, together with bone marrow cells, in the micronucleus assay. Both model chemicals induced micronuclei in the colon, which is the target organ of these carcinogens, after short- and long-term treatment(s). The results demonstrate the target specificity of micronucleus induction and the assay using organs other than bone marrow will play an important role in understanding the mechanism of carcinogenicity and predicting new carcinogenic agents.

    更新日期:2020-01-13
  • Pharmacokinetics of oseltamivir phosphate and oseltamivir carboxylate in non-pregnant and pregnant rhesus monkeys
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-09
    Lucie Loukotková; Mallikarjuna Basavarajappa; Annie Lumen; Rosemary Roberts; Donald Mattison; Suzanne M. Morris; Jeffrey Fisher; Frederick A. Beland; Gonçalo Gamboa da Costa

    Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not clear if the significant physiological alterations associated with pregnancy affect the pharmacokinetics of oseltamivir and, thus, warrant different dosing regimens to assure efficacy. In this study, we investigated the suitability of rhesus macaques as an animal model for studying oseltamivir pharmacokinetics during all trimesters of pregnancy in comparison to pre-pregnant conditions. Specifically, we compared the pharmacokinetics of oseltamivir and its pharmacologically active metabolite oseltamivir carboxylate in rhesus monkeys after intravenous and nasogastric administration of 2.5 mg oseltamivir phosphate/kg body weight given prior to and during the first, second, and third trimesters of pregnancy. Pregnancy had only a modest effect upon the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate. Monkeys treated intravenously in the third trimester had a reduction in Vd and CL, compared to non-pregnant monkeys. These changes did not occur in the other two trimesters. Pregnant monkeys treated intravenously had 20–25% decrease in AUC0-∞ of oseltamivir carboxylate and a corresponding increase in Vd and CL. Pregnant monkeys treated nasogastrically with oseltamivir phosphate demonstrated a pattern that recapitulated intravenous dosing. Taken together these data indicate that rhesus monkeys are an acceptable model for studying drug-pregnancy interactions.

    更新日期:2020-01-10
  • Plasticizer migration from children's toys, child care articles, art materials, and school supplies
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-07
    Michael A. Babich; Charles Bevington; Matthew A. Dreyfus

    Dialkyl phthalates, including diisononyl phthalate (DINP), have been used as plasticizers in children's products made from polyvinyl chloride (PVC), such as teethers and toys. Children may be exposed to phthalates when handling or mouthing PVC products because plasticizers are not covalently bound. The Consumer Product Safety Improvement Act of 2008 prohibited certain phthalates from use in child care articles and children's toys. Thus, manufacturers have changed to other plasticizers or non-PVC plastics and there is interest in evaluating the potential health risks of alternative plasticizers. In 2008, CPSC staff purchased 63 children's products comprising 129 individual pieces (articles). Plastics identified by FTIR included PVC, polypropylene, polyethylene, and acrylonitrile butadiene styrene. Plasticizers identified by in the 38 PVC articles included acetyltributyl citrate (ATBC) (20); di (2-ethylhexyl) terephthalate (DEHT) (14); 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINX) (13); 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TPIB) (9); di (2 ethyhexyl) phthalate (DEHP) (1); and DINP (1). Half of the tested articles contained multiple plasticizers. CPSC measured migration rates using the Joint Research Centre method. Migration rates correlated roughly with plasticizer concentration and inversely with the molecular mass of the plasticizer. We then combined the migration rates to estimate children's exposure to plasticizers in toys and child care articles, and estimated margins of exposure. All margins of exposure were >1,000, suggesting a low risk potential. However, the plasticizers in this study have multiple uses. Exposure from other sources and routes of exposure will be considered in future work.

    更新日期:2020-01-07
  • Maternal exposure to ibuprofen can affect the programming of the hypothalamus of the male offspring
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2020-01-03
    Paola da Silva Balin; Bárbara Campos Jorge; Andressa Rejani Ribeiro Leite; Cibele Santos Borges; Eunice Oba; Erick José Ramo Silva; Aline Lima de Barros; José de Anchieta Castro Horta Júnior; Arielle Cristina Arena
    更新日期:2020-01-04
  • The accessibility of data on environmental risk assessment of pharmaceuticals – are environmental risk assessments information on emissions with respect to international and European environmental information law?
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-29
    Kim Oelkers

    In the pharmaceutical sector, the right of access to environmental information is in most cases not feasible as the authorisation holders refer to commercially/industrial confidential information (CCI). However, CCI can not refuse access to environmental risk assessments (ERAs) if ERAs are to be classified as information on emissions. Pharmaceuticals inevitably enter the environment as a consequence of their intended use. This release is calculated in the ERA as predicted environmental concentration when a pharmaceutical is approved. The release of pharmaceuticals into the environment falls consequently under the term ‘emissions into the environment’. In addition, the ERAs assessing the risk of this release are to be classified as ‘information on emissions into the environment’. Therefore, the practiced secrecy of ERAs of pharmaceuticals and their official assessment reports is incompatible with Art. 4 Aarhus Convention, and the European and national implementing provisions for this article, which require access to such environmental information on emissions for everyone, irrespective of whether they concern CCI. With this legal disclosure obligation of ERAs, there is an enforceable right of access for everyone, which shows the necessity for establishing a publicly accessible database based on active pharmaceutical ingredients with substantiated information on the ERAs.

    更新日期:2019-12-29
  • In vitro and in vivo effects of 5-aminotetrazole (5-AT), an energetic compound
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-26
    Valerie H. Adams; Matthew A. Bazar; Emily N. Reinke; Angela R. Buckalew; William S. Eck

    Perchlorate is an important oxidizer used in propellants, pyrotechnics, and as a gas generator in commercial airbags, fireworks, and roadside flares. It is highly water soluble interferes with thyroidal iodide uptake and is an environmental contaminant. By changing the reaction chemistry, 5-aminotetrazole (5-AT) and nitrates replace perchlorate in some propellants. The short term toxicity of 5-AT was evaluated. Using a modified Ames assay, 5-AT was not mutagenic with or without S9 metabolic activation. 5-AT was considered “slightly toxic” with an EC50 of 28.8 mg 5-AT/L for a 15 min exposure in Aliivibrio fischeri. In the in vitro sodium iodide symporter test, 5-AT did not inhibit the uptake of iodine. In the acute rat oral test, no adverse effects and no mortalities were observed at the limit dose of 2000 mg 5-AT/kg. In the 14-day sub-acute study, there were no clinical signs of toxicity or morbidity up to 623 mg 5-AT/kg-day; the highest dose tested. No differences were observed in hematology, clinical chemistry, organ weight, body weight, food consumption, histopathology, or DNA damage (peripheral blood micronucleus assay) of treatments compared with controls. The No Observed Adverse Effect Level (NOAEL) was 623 mg 5-AT/kg-day, the highest dose in the subacute oral bioassay.

    更新日期:2019-12-27
  • Transgene expression in sprayed and non-sprayed herbicide-tolerant genetically engineered crops is equivalent
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-26
    Brandon J. Fast; Guomin Shan; Satyalinga Srinivas Gampala; Rod A. Herman

    Regulations governing the safety assessment of genetically engineered (GE) crops require studies that measure the expression levels of the transgene products (proteins and double-stranded RNA) in the GE crop; furthermore, the regulations also often mandate the inclusion of an entry of the GE crop that is sprayed with the herbicide to which tolerance was engineered and a non-sprayed entry of the GE crop in said studies. The hypothesized unique risk of altered transgene expression in response to application of herbicides related to herbicide-tolerant GE crops, compared with application of other herbicides, is not readily apparent. Field studies were conducted with GE maize, soybean, and cotton breeding stacks containing multiple herbicide tolerance traits; studies included plots that were sprayed with the trait-related herbicides and plots that were unsprayed. The GE herbicide-tolerance traits and complimentary herbicides investigated here comprise the majority of those that are currently in commercial use. Transgene product expression was characterized in crop tissues that were collected throughout the growing season. Results confirm the expectation, which is based on the fact that modes of action and regulatory elements in the genetic constructs of the herbicide-tolerance traits are well understood, that applying herbicides associated with GE herbicide-tolerance traits does not meaningfully affect transgene expression. These findings call into question the routine requirement for the inclusion of herbicide sprayed and non-sprayed entries in transgene-expression studies designed to support risk assessment.

    更新日期:2019-12-27
  • 更新日期:2019-12-27
  • Oral repeated-dose toxicity studies of BIA 10–2474 in beagle dogs
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-23
    Jerry F. Hardisty; Stephen B. Harris; Wallace A. Hayes; Klaus Weber

    BIA 10–2474 is a novel fatty acid amide hydrolase inhibitor developed for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10–2474 and others displayed neurological signs. We describe here the toxicology studies in beagle dogs that supported phase I testing of BIA 10–2474 in humans. A Maximum Tolerated Dose (MTD) study using once-a-day oral (capsule) application of BIA 10–2474 was first conducted to establish suitable dose levels for subsequent studies. Based on these results, 100 mg/kg/day was considered to be the MTD. The 4-week oral (capsule) toxicity study with a 3-week recovery period for BIA 10–2474 was therefore carried out at 20, 50 or 100 mg/kg/day. There were no changes recorded at 50 mg/kg/day and this was considered the oral No Observed Effect Level (NOEL) for four-week once-a-day capsule administration to Beagle dogs. At 100 mg/kg/day, the dose-limiting findings consisted of clinical symptoms including tremor, loss of balance, abnormal gait, decreased motor activity, weakness, vomits, salivation increase and miosis, increased severity of thymic atrophy/involution, and moderate acute, focal/multifocal bronchopneumonia in lungs of three animals. In a 13-week oral (capsule) toxicity study in the Beagle dog with a 6-week recovery period, using the same dose levels, clinical signs were recorded during treatment with BIA 10–274 at 50 and 100 mg/kg/day. The most frequent signs included difficulty breathing, respiratory sounds (with or without auscultation) and cough. Incoordination of the hind limbs with absence of correction reflex were also observed on some occasions. As a result, the 50 and 100 mg/kg/day doses were reduced to 35 and 50 mg/kg/day respectively on day 37. Because of the continued signs, the doses in both groups were further reduced to 20 mg/kg/day from day 77. Under the conditions of this study and given the severe signs recorded in groups treated at 100-50-20 and 50-35-20 mg/kg/day and only very occasional presence of signs in the group treated for the 13-week period at 20 mg/kg/day (abnormal respiratory sounds once in two animals), the dose of 20 mg/kg/day was considered the No Observed Adverse Effect Level (NOAEL).

    更新日期:2019-12-23
  • The absence of genotoxicity of a novel fatty acid amide hydrolase inhibitor, BIA 10–2474
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-19
    A. Wallace Hayes; Jerry F. Hardisty; Stephen B. Harris; Klaus Weber

    In 2016 one person died and others had neurological sequelae during a clinical trial with BIA 10–2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-lH-imidazol-4-yl)pyridine 1-oxide), a novel fatty acid amide hydrolase (FAAH) inhibitor being developed for the treatment of medical conditions such as pain. Prior to the clinical trial a full battery of regulatory toxicology tests were carried out and this paper describes the genotoxicity/mutagenicity tests undertaken with BIA 10–2474 using the Ames (Salmonella typhimurium) reverse mutation test, the Escherichia coli WP2uvrA forward mutation test, an in vitro chromosome damage assay in human lymphocytes, and an in vivo micronucleus test in mice. All tests were conducted with and without a rat liver S9 metabolic activation system. None of the test results were judged to be positive with regards to the mutagenicity/genotoxicity of BIA 10–2474 making it unlikely that any such effect was involved in the toxicity observed in the clinic.

    更新日期:2019-12-20
  • Oral repeated-dose toxicity studies of BIA 10–2474 in CD-1 mice
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-19
    A. Wallace Hayes; Peter Pressman; Jerry F. Hardisty; Stephen B. Harris; Klaus Weber

    We independently and retrospectively reviewed three studies that evaluated the toxicity of BIA 10–2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-lH-imidazol-4-yl)pyridine 1-oxide), a novel fatty acid amide hydrolase (FAAH) inhibitor in male and female CD-1 mice based upon raw data obtained from Bial Portela & Companhia S.A. (São Mamede do Coronado, Portugal). These studies were carried out prior to the clinical trial with BIA 10–2474 and formed part of the regulatory submission. An initial oral dose range-finding study with BIA 10–2474 showed that doses from 600 mg/kg/day were poorly tolerated with a high mortality rate and signs of weakness, prostration, labored breathing, clear lacrimation, tachypnea/bradypnea and decreased activity. At lower doses (100 and 300 mg/kg/day) there were few signs but post-mortem analysis showed increased liver weight. In a 28-day study a third of the animals receiving 500 mg/kg/day died or required euthanasia, with similar signs to those seen in the dose-range finding study. At lower doses (i.e. 100 and 300 mg/kg/day) there were few clinical signs although there were dose-related decreases in erythrocyte count and hemoglobin. Histopathology was seen in the 300 and 500 mg/kg/day groups and included hepatocellular hypertrophy (with increased liver weight), nephropathy and enterocyte vacuolation. Finally, in the 13-week oral gavage study, BIA 10–2474 was administered to CD-1 mice of both sexes at dose levels of 25, 75 and 150 mg/kg/day. Under these conditions, there were almost no clinical signs apart from a tendency to increase body-weight. Cholesterol was increased at 75 and 150 mg/kg and remained high after recovery. Liver and spleen weights increased at 75 and 150 mg/kg/day. Histopathologically, there was a dose-dependent increase in sciatic nerve and myofiber degeneration, hepatocellular hypertrophy, nephropathy and inflammatory loci in the bladder. The nerve damage and nephropathy seen at 150 mg/kg/day persisted after a 4-week recovery period. Toxicokinetic analysis in the 4- and 13-week studies showed that exposure was broadly dose-proportional with no evidence of accumulation. On the basis of the changes seen during the 13-week study, the NOAEL was established at 75 mg/kg/day.

    更新日期:2019-12-20
  • Rat 90-day oral toxicity study of a novel coccidiostat – Ethanamizuril
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-13
    Keyu Zhang; Xiaoyang Wang; Mi Wang; Yingchun Liu; Lifang Zhang; Chunmei Wang; Chenzhong Fei; Juan Li; Feiqun Xue

    In the current study, to support the safety assessment of ethanamizuril as a new potent anticoccidial agent of triazine compounds, a 90-day repeated-dose oral toxicity assay of ethanamizuril was investigated. Treatment related clinical signs of alopecia on back and neck have been observed in some male and female at the 65 and 130 mg/kg dose groups. The body weight and feed conversion efficacy of 65 and 130 mg/kg females and 65 mg/kg males were significantly increase than those of the control in treatment time, but noted decreased in the 130 mg/kg males. Dose related changes of hematologic and biochemical parameters such as MCV, MCH, TG, and the significant increased in the organ weight and the relative organ weight of the liver, kidney, heart, lung and spleen in both genders in the 65 and 130 mg/kg treated groups were observed. Furthermore, histopathological observations revealed that 65 and 130 mg/kg ethanamizuril induced pathological damage such as hepatocyte steatosis and focal necrosis, renal tubular atrophy, tubule protein casts. Fortunately, the observed toxicities were recoverable in convalescence. The results indicated that liver, kidneys and lung were the main target organs. The NOAEL of ethanamizuril for rats was estimated to be 20 mg/kg dietary dose level.

    更新日期:2019-12-13
  • Toxicokinetic testing strategies to demonstrate bone marrow exposure in in vivo micronucleus study for genotoxicity assessment of agrochemicals
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-10
    Gopinath C. Nallani, Zhiwei Liu, Appavu Chandrasekaran

    Following adoption of the new OECD test guideline (TG) 474 for the in vivo mammalian erythrocyte micronucleus (MN) test (29 July 2016), demonstration of exposure of target tissue (bone marrow) is required, if the test result is negative i.e. no cytogenetic damage. It implies that for many active ingredients, relevant metabolites or significant impurities with existing in vivo MN tests resulting in negative genotoxicity findings, evidence of target tissue exposure may be lacking and is considered a data gap in regulatory reviews. We present here toxicokinetic (TK) testing strategies for the design and conduct of studies that would demonstrate evidence of delivery of the test substance to the bone marrow. To illustrate this, three examples are presented with methods utilized under each scenario. We also propose a decision tree that may help design suitable TK studies to establish evidence of bone marrow exposure.

    更新日期:2019-12-11
  • Oral repeated-dose toxicity studies of BIA 10–2474 in cynomolgus monkeys
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-06
    Klaus Weber, Rüdiger Häcker, Jerold F. Hardisty, Stephen B. Harris, A. Wallace Hayes

    BIA 10–2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10–2474 and others displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys. Maximum Tolerated Dose (MTD) studies and a preliminary 14-day study by oral (capsule) administration of BIA 10–2474 established a dose between 90 and 120 mg/kg/day as a suitable high dose for a subsequent regulatory toxicity studies. An up-titration scheme was used to achieve these doses. The dose-limiting effect was the early sacrifice for ethical reasons of monkeys at doses from 125 mg/kg/day upwards. Thereafter, regulatory 4- and 13-week oral gavage toxicity studies followed by a 2- or a 4-week recovery period, respectively, were performed. In both cases a 3-4-week up-titration period was used prior to repeat dosing with the target doses. One female was euthanised during the up-titration period after receiving 9 administrations of 75 mg/kg as a result of bleeding erosion on the feet and hands and ulceration on the tongue. These signs were not seen in any other monkeys during these studies. Doses of 10, 50 or 100 mg/kg/day were administered during the 4-week study and clinical signs related to the pharmacological action of BIA 10–2474 (e.g., tremors and weakness, incoordination and loss of balance, reduction in food intake and reduced body weight) were observed in several monkeys from the intermediate and high dose. Histological alterations consisted of axonal dystrophy in the fasciculus cuneatus (dorsal medulla oblongata) characterized by swollen axons and myelin sheath edema, edema in the pars nervosa of the pituitary gland and vacuolation of Meissner's plexus ganglia in all gastrointestinal segments. All lesions recovered and a dose of 100 mg/kg/day was considered to be the NOAEL. In the 13-week oral study the monkeys received BIA 10–2474 daily by gavage at a dose of 6.25, 37.5 or 75 mg/kg/day. Similar clinical signs and histological alterations as noted in monkeys of the 28-day study were observed in monkeys at 37.5 or 75 mg/kg/day. All findings recovered, and the dose of 75 mg/kg/day was considered the NOAEL.

    更新日期:2019-12-07
  • Bioaccessibility of nickel and cobalt in synthetic gastric and lung fluids and its potential use in alloy classification
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-05
    Katherine E. Heim, Ruth Danzeisen, Violaine Verougstraete, Frédéric Gaidou, Tony Brouwers, Adriana R. Oller
    更新日期:2019-12-05
  • Chemistry, metabolism and pharmacology of carcinogenic alkaloids present in areca nut and factors affecting their concentration
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-12-02
    Alpana K. Gupta, Sonam Tulsyan, Nisha Thakur, Vishwas Sharma, Dhirendra N. Sinha, Ravi Mehrotra

    Areca Nut (AN), the seed of tropical palm tree Areca catechu, is a widely chewed natural product with estimated 600 million users across the world. Various AN products, thriving in the market, portray ‘Areca nut’ or ‘Supari’ as mouth freshener and safe alternative to smokeless tobacco. Unfortunately, AN is identified as a Group 1 human carcinogen by International Agency for Research on Cancer (IARC). Wide variation in the level of alkaloids, broadly ranging from 2 to 10 mg/gm dry weight, is observed in diverse variety of AN sold worldwide. For the first time, various factors influencing the formation of carcinogenic alkaloids in AN at various stages, including during the growth, processing, and storage of the nut, are discussed. Current review illustrates the mechanism of cancer induction by areca alkaloids in humans and also compiles dose-dependent pharmacology and toxicology data of arecoline, the most potent carcinogenic alkaloid in AN. Careful monitoring of the arecoline content in AN can potentially be used as a tool in product surveillance studies to identify the variations in characteristics of various AN sample sold worldwide. The article will help to generate public awareness and sensitize the government bodies to initiate campaigns against AN use and addiction.

    更新日期:2019-12-02
  • Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: Dual regulation of the PI3K/AKT and MAPK pathways
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-26
    Ning Zhang, Xiaoyan Liu, Lili Zhuang, Xuemei Liu, Huishan Zhao, Yinghua Shan, Zhenteng Liu, Fenghua Li, Yilin Wang, Jianye Fang

    Berberine has been found to exhibit an array of pharmacological activities relating to the lowering of blood glucose and the treatment of polycystic ovarian syndrome (PCOS). The mechanism underlying these activites, however, is poorly understood. In the present study, female Sprague-Dawley (SD) rats were given oral letrozole to establish a model of insulin-resistant PCOS, and animals were then randomized into untreated or berberine-treated groups (400, 200, or 100 mg/kg). After 28 days, we measured homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity index (ISI) values in these animals. We further conducted H&E staining of ovarian tissues, assessed mRNA expression of glucose transporter 4 (GLUT4) via real time PCR, and used Western blotting to measure GLUT4 and PI3K/AKT and MAPK pathway protein levels. Berberine treatment was able to help restore HOMA-IR and ISI values to normal levels while simultaneously bolstering the expression of GLUT4. Normal ovarian morphology was also restored upon berberine treatment. We further found that 400 mg/kg berberine treatment was associated with activation of PI3K/AKT signaling and suppression of the MAPK pathway. In conclusion, berberine has the potential to reduce PCOS pathology and IR values in a rat model system through a mechanism linked to GLUT4 upregulation via PI3K/AKT activation and MAPK pathway suppression.

    更新日期:2019-11-26
  • Deriving safe short-term chemical exposure values (STEV) for drinking water
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-25
    Frederic D.L. Leusch, Stuart J. Khan, Daniel Deere, David Cunliffe, Peta A. Neale, Andrew Humpage

    Small and brief exceedances of chemicals above their guideline values in drinking water are unlikely to cause an appreciable increased risk to human health. As a result, short-term exposure values (STEV) can be derived to help decide whether water can still be supplied to consumers without adverse health risks. In this study, three approaches were applied to calculate and compare STEV for pesticides. The three approaches included basing a STEV on the acute reference dose (ARfD) (Approach 1), removing conventional attribution rates and uncertainty factors from current guideline values (Approach 2) and extrapolating 1 d and 7 d no observed adverse effect levels (NOAEL) from existing toxicity data using a log-linear regression (Approach 3). Despite being very different methods, the three approaches produced comparable STEV generally within an order of magnitude, which often overlapped with other existing short-term exposure values such as short-term no adverse response levels (SNARL) and health advisories (HA). The results show that adjusting the current guideline value using standard extrapolation factors (Approach 2) often produced the most conservative values. Approach 2 was then applied to two other chemical classes, disinfection by-products (DBPs) and cyanotoxins, demonstrating the wider applicability of the approach.

    更新日期:2019-11-26
  • Arsenic exposure: A public health problem leading to several cancers
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-23
    I. Palma-Lara, M. Martínez-Castillo, J.C. Quintana-Pérez, M.G. Arellano-Mendoza, F. Tamay-Cach, O.L. Valenzuela-Limón, E.A. García-Montalvo, A. Hernández-Zavala

    Arsenic, a metalloid and naturally occurring element, is one of the most abundant elements in the earth's crust. Water is contaminated by arsenic through natural sources (underground water, minerals and geothermal processes) and anthropogenic sources such as mining, industrial processes, and the production and use of pesticides. Humans are exposed to arsenic mainly by drinking contaminated water, and secondarily through inhalation and skin contact. Arsenic exposure is associated with the development of vascular disease, including stroke, ischemic heart disease and peripheral vascular disease. Also, arsenic increases the risk of tumors of bladder, lungs, kidneys and liver, according to the International Agency for Research on Cancer and the Food and Drug Administration. Once ingested, an estimated 70–90% of inorganic arsenic is absorbed by the gastrointestinal tract and widely distributed through the blood to different organs, primarily to the liver, kidneys, lungs and bladder and secondarily to muscle and nerve tissue. Arsenic accumulates in the organs, especially in the liver. Its excretion mostly takes place through urination. The toxicokinetics of arsenic depends on the duration of exposure, pathway of ingestion, physicochemical characteristics of the compound, and affected biological species. The present review outlines of arsenic toxic effects focusing on different cancer types whit highest prevalence's by exposure to this metalloid and signaling pathways of carcinogenesis.

    更新日期:2019-11-26
  • Developmental and reproductive toxicity studies of BIA 10-2474
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-20
    Stephen B. Harris, Jerold F. Hardisty, A. Wallace Hayes, Klaus Weber

    A series of regulatory studies were carried out to investigate the effects of the FAAH inhibitor BIA 10–2474 on fertility, embryo-fetal toxicity and pre- and post-natal development in rats and rabbits. Despite some reductions in sperm count in rats from 50 mg/kg, there were no major changes in male fertility up to 100 mg/kg. In female rats administered up to GD6, there were increases in pre-implantation loss at 50 and 100 mg/kg but neither post-implantation loss nor early embryonic development was affected. In contrast, when administered to female rats during pregnancy (GD6-GD17), BIA 10–2474 at 75 mg/kg/day reduced food consumption resulting in weight loss, increased post-implantation loss and reduced mean fetal body weight. In rabbits, the same maternal toxicity was seen but there were no effects in this species on post-implantation loss or fetal body weights. There were no teratological effects clearly due to BIA 10–2474 and developmental milestones and behavior of offspring were not affected. When administered during pregnancy and lactation (GD6-PND20), some post-implantation loss was seen from 20 mg/kg/day, but developmental milestones and behavior of the offspring were not affected, although males tended to have lower body weight. Based on these data the NOAEL for parental fertility was established as 50 mg/kg/day, the maternal NOAEL during pregnancy was 25 mg/kg/day in rats and developmental NOAEL was 25 and 75 mg/kg/day in rats and rabbits, respectively. When administered during post-natal development to rats the maternal NOAEL was 6 mg/kg/day. The parental reproductive NOAEL, the NOAEL for viability and growth of the F1 offspring, the F1 parental NOAEL and the F1 reproductive NOAEL were all considered to be 20 mg/kg/day.

    更新日期:2019-11-21
  • Send harmonization & cross-study analysis: A proposal to better harvest the value from send data
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-20
    Mark A. Carfagna, Thomas G. Bjerregaard, Tamio Fukushima, William Houser, Cheryl Sloan, Kevin Snyder, Jesse Anderson, Todd Page
    更新日期:2019-11-20
  • Oral repeated-dose toxicity studies of BIA 10–2474 in Wistar rat
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-20
    A. Wallace Hayes, Jerold F. Hardisty, Stephen B. Harris, Yoshimasa Okazaki, Klaus Weber

    BIA 10–2474 is a novel fatty acid amide hydrolase (FAAH) inhibitor developed for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10–2474 and four other subjects displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial, we report here the preclinical toxicology studies examining once-a-day oral administration of BIA 10–2474 to male and female Wistar rats. These included a 14-day dose range finding (150, 200 and 250 mg/kg/day), a 4-week study (30, 90 and 150 mg/kg/day) and 13- and 26-week studies (both at 10, 30 and 90 mg/kg/day). The 13- and 26-week studies also included a 4-week recovery arm and a toxicokinetic arm for the parent compound, BIA 10–2474, and the two major metabolites (BIA 10–2445 and BIA 10–2583) were also measured in the 26-week study. At 150 mg/kg and below, all animals survived the scheduled treatment periods although neurological side-effects (abnormal or stiff gait, dragging of fore- or hind-limbs) were seen at 150 mg/kg in both the dose-range finding and 4-week studies. At 90 mg/kg/day, even up to 26-weeks treatment, no clinical signs were seen apart from some decreases in body weight gain. A number of consistent hematological and biochemical changes were noted which were considered related to treatment with BIA 10–2474. Morphologically, in the 4-week study, except for a slight gliosis in the hippocampus of one female at 150 mg/kg, no CNS histopathology was observed; hippocampus gliosis was not observed in subsequent studies. In the 13-week study axonal swelling was present in the medulla oblongata in about half the animals at 90 mg/kg/day and this increased to nearly all the rats at 90 mg/kg/day in the 26-week study. Additional signs seen only in the 26-week study at 90 mg/kg/day included axonal swelling of the fasiculus gracilis and vacuolar changes in the medulla oblongata and ventral commissure of the 3rd ventricle. Other findings included vacuolar degeneration in the ganglia of the GI tract, salivary glands, prostate gland, uterus, and parathyroid glands. The pituitary gland showed edema and mitotic figures in the pars nervosa. These observations outside the CNS were seen in most rats at 90 and 150 mg/kg/day independent of study duration. At 30 mg/kg/day, most of these observations were only seen in isolated cases except for the vacuolar degeneration in GI tract ganglia, which was absent at this dose after 4 weeks treatment but was present in almost all rats at 13 and 26 weeks. Hepatocellular hypertrophy and nephropathy were seen across all studies and the extent of these changes was similar in the 13- and 26-week studies. Most findings resolved after the 4-week recovery periods except for the axonal swelling seen in the medulla oblongata and spinal cord. BIA 10–2474 exposure was markedly higher than the exposure to either metabolite, BIA 10–2445 (19- to 192-fold) and BIA 10–2583 (63- to 526-fold). Exposure to metabolites differed between sexes with higher concentrations of BIA 10–2445 in females compared to males, but the inverse for BIA 10–2583. Although a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day was concluded following the 4-week study, the histopathological findings at that dose in the 13- and 26-week studies resulted in the NOAEL being determined to be 10 mg/kg/day.

    更新日期:2019-11-20
  • Safety evaluation of Bacillus coagulans SNZ 1969 in Wistar rats
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-18
    Anantha Samwarnarao Metlakunta, Raunak Jay Soman

    Bacillus coagulans SNZ 1969 is a rod-shaped, slightly acidophilic, gram-positive, spore forming and highly resilient bacteria. B. coagulans SNZ 1969 has GRAS (Generally Recognized As Safe) status for use as a probiotic in foods (US FDA number GRN-597). The present study was aimed to assess the safety of a proprietary strain Bacillus coagulans SNZ 1969 by conducting acute and sub-acute 28 days repeated dose oral toxicity studies in Wistar Rats. In the acute toxicity study, the rats were orally fed with 2000 mg/kg body weight (BW) (5 × 1011 CFU/g) of B. coagulans SNZ 1969 as a single dose to determine the LD50 values. In the sub-acute repeated dose toxicity study, six groups of experimental rats received 250, 500, 1000 mg/kgBW/day (5 × 1011 CFU/g) of the test item for 28 consecutive days. The control animals received only water. Four groups of rats were sacrificed after 28 days and the remaining two groups were kept as recovery groups and sacrificed after 42 days. The results of these study indicate that there were no treatment related changes in any of the parameters studied i.e. clinical signs, body weight, food intake, urinalysis, hematological examinations, clinical biochemistry, gross pathology and histopathology after 28 days of repeated administration. Based on the results it was concluded that the LD50 of Bacillus coagulans SNZ 1969 is more than 2000 mg/kg body weight and the NOAEL derived from this study was 1000 mg/kg/day for 28 days, this corresponds to the 5 × 1011 CFU/kg.

    更新日期:2019-11-18
  • 更新日期:2019-11-18
  • Chemical compounds causing severe acute toxicity in heavy liquids used for intraocular surgery
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-14
    Girish K. Srivastava, Cristina Andrés-Iglesias, Rosa M. Coco, Ivan Fernandez-Bueno, Jesús Medina, Juan García-Serna, Antonio Dueñas, Fernando Rull, J. Carlos Pastor
    更新日期:2019-11-14
  • Qualification of impurities based on metabolite data
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-14
    Lars Weidolf, Thomas Andersson, Joel P. Bercu, Andreas Brink, Susanne Glowienke, James Harvey, Martin A. Hayes, Pascale Jacques, Chuang Lu, Nenad Manevski, Wolfgang Muster, Raphael Nudelman, Ron Ogilvie, Jenny Ottosson, Andrew Teasdale, Bruce Trela
    更新日期:2019-11-14
  • A 26-week 20(S)-ginsenoside Rg3 oral toxicity study in Beagle dogs
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-11
    Yonglin Gao, Guangfei Wang, Tong Wang, Guisheng Li, Jian Lin, Liqin Sun, Xuran Wu, Xilin Sun, Hongbo Wang, Chunmei Li, Jingwei Tian, Jing Zhu, Kezhou Wang, Susan Cho

    20(s)-ginsenoside Rg3 is a red ginseng-derived compound with the formula C42H72O13 that has been increasingly used by humans, leading to safety concerns regarding this use. In the current study, we conducted a 26-week study during which 20(S)-ginsenoside Rg3 (0, 7, 20, or 60 mg/kg) was continuously administered orally to Beagle dogs in order to explore its toxicity in these animals, with control dogs receiving a vehicle capsule. In total, 10 dogs received each dose of this compound (n = 5 male, n = 5 female per dose). Animals were continuously monitored for a 26-week administration period and a subsequent 4-week follow-up recovery period. At the end of study, we observed no evidence of 20(S)-ginsenoside Rg3 toxicity in clinical indications, body weight, food intake, ophthalmoscopy, electrocardiogram, urinalysis, hematology, serum biochemistry, gross and histopathology findings. However, the kidney relative weight of animals receiving 60 mg/kg of compound was significantly elevated relative to control animals (5.15 ± 0.88‰ vs. 4.11 ± 0.59‰. P < 0.05), and this effect was reversed after 4-week recovery period. Based on these results, the NOAEL value for orally administered 20(S)-ginsenoside Rg3 in dogs is 20 mg/kg.

    更新日期:2019-11-13
  • A cross-sector call to improve carcinogenicity risk assessment through use of genomic methodologies
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-11
    Carole L. Yauk, Alison H. Harrill, Heidrun Ellinger-Ziegelbauer, Jan Willem van der Laan, Jonathan Moggs, Roland Froetschl, Frank Sistare, Syril Pettit

    Robust genomic approaches are now available to realize improvements in efficiencies and translational relevance of cancer risk assessments for drugs and chemicals. Mechanistic and pathway data generated via genomics provide opportunities to advance beyond historical reliance on apical endpoints of uncertain human relevance. Published research and regulatory evaluations include many examples for which genomic data have been applied to address cancer risk assessment as a health protection endpoint. The alignment of mature, robust, reproducible, and affordable technologies with increasing demands for reduced animal testing sets the stage for this important transition. We present our shared vision for change from leading scientists from academic, government, nonprofit, and industrial sectors and chemical and pharmaceutical safety applications. This call to action builds upon a 2017 workshop on “Advances and Roadblocks for Use of Genomics in Cancer Risk Assessment.” The authors propose a path for implementation of innovative cancer risk assessment including incorporating genomic signatures to assess mechanistic relevance of carcinogenicity and enhanced use of genomics in benchmark dose and point of departure evaluations. Novel opportunities for the chemical and pharmaceutical sectors to combine expertise, resources, and objectives to achieve a common goal of improved human health protection are identified.

    更新日期:2019-11-13
  • Preclinical safety evaluation of triacylglycerol lipase QLM from Burkholderia ubonensis
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-11
    Alastair Mak, Ryan R. Simon

    Triacylglycerol lipases are well characterized enzymes that catalyze the hydrolysis of fats. They are biotechnologically relevant enzymes and are used in a wide range of practical applications in industry. Lipase produced from Burkholderia ubonensis (strain PL266-643-301) (Lipase QLM) is being investigated for use as a processing aid in multiple food applications and may therefore be present at trace level in finished food products. A battery of toxicological studies was therefore conducted on Lipase QLM to support its safe use in food. Lipase QLM was not genotoxic or mutagenic in an in vitro bacterial reverse mutation test and chromosome aberration test. Additionally, no test article-related adverse effects were observed in clinical observations, body weight, food consumption, ophthalmology, hematology, blood chemistry, urinalysis, and macroscopic and microscopic findings in a subchronic toxicity study in rats administered Lipase QLM in the diet at levels of 0%, 0.8%, 2%, and 5% Lipase QLM. The no-observed-adverse-effect level was therefore considered to be 5% Lipase QLM in both sexes [3357.2 and 3777.6 mg/kg body weight/day (2756.3 and 3101.4 mg total organic solids/kg body weight/day) in males and females, respectively] under the test conditions, which supports the safety of this ingredient for use in food for human consumption.

    更新日期:2019-11-13
  • Acute and subacute (28 days) toxicity of green coffee oil enriched with diterpenes cafestol and kahweol in rats
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-09
    Naila Albertina de Oliveira, Thaisa Meira Sandini, Heber Peleg Cornelio-Santiago, Elaine Cristina Lanzoni Martinelli, Leonilda Ester Reinert Raspantini, Paulo Cesar Raspantini, Cláudia Momo, Alessandra Lopes de Oliveira, Heidge Fukumasu
    更新日期:2019-11-11
  • U.S. food & Drug Administration's interim reference levels for dietary lead exposure in children and women of childbearing age
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-07
    Brenna M. Flannery, Laurie C. Dolan, Dana Hoffman-Pennesi, Alexandra Gavelek, Olivia E. Jones, Richard Kanwal, Beverly Wolpert, Kathleen Gensheimer, Sherri Dennis, Suzanne Fitzpatrick

    Reducing lead exposure is a public health priority for the US Food and Drug Administration as well as other federal agencies. The goals of this research were to 1) update the maximum daily dietary intake of lead from food, termed an interim reference level (IRL), for children and for women of childbearing age (WOCBA) and 2) to confirm through a literature review that with the exception of neurodevelopment, which was not evaluated here, no adverse effects of lead consistently occur at the blood lead level (BLL) associated with the IRL. Because no safe level of lead exposure has yet been identified for children's health, the IRLs of 3 μg/day for children and 12.5 μg/day for WOCBA were derived from the Centers for Disease Control and Prevention reference value of 5 μg/dL BLL, the level at which public health actions should be initiated. The literature review showed that no adverse effects of lead consistently occurred at the BLL associated with the IRLs (0.5 μg/dL). The IRLs of 3 μg/day for children and 12.5 μg/day for WOCBA should serve as useful benchmarks in evaluating the potential for adverse effects of dietary lead.

    更新日期:2019-11-08
  • The urinary metabolic profile of diethylene glycol methyl ether and triethylene glycol methyl ether in Sprague-Dawley rats and the role of the metabolite methoxyacetic acid in their toxicity
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-06
    Jeffrey R. Kelsey, Nicole H.P. Cnubben, Jan J.P. Bogaards, René B.H. Braakman, Leo L.P. van Stee, Karen Smet

    Ethylene glycol ethers are a well-known series of solvents and hydraulic fluids derived from the reaction of ethylene oxide and monoalcohols. Use of methanol as the alcohol results in a series of mono, di and triethylene glycol methyl ethers. The first in the series, monoethylene glycol methyl ether (EGME or 2-methoxyethanol) is well characterised and metabolises in vivo to methoxyacetic acid (MAA), a known reproductive toxicant. Metabolism data is not available for the di and triethylene glycol ethers (DEGME and TEGME respectively). This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives <4 h for each one. Both substances were also found to produce small amounts of MAA (∼0.5% for TEGME and ∼1.1% for DEGME at doses of 1000 mg/kg) through cleavage of the ether groups in the molecules. These small amounts of MAA produced can explain the effects seen at high doses in reproductive studies using DEGME and TEGME.

    更新日期:2019-11-06
  • State of the science on alternatives to animal testing and integration of testing strategies for food safety assessments: Workshop proceedings
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-06
    Agnes L. Karmaus, Heidi Bialk, Suzanne Fitzpatrick, Mansi Krishan

    Rapidly evolving technological methods and mechanistic toxicological understanding have paved the way for new science-based approaches for the determination of chemical safety in support of advancing public health. Approaches including read-across, high-throughput screening, in silico models, and organ-on-a-chip technologies were addressed in a 2017 workshop focusing on how scientists can move effectively toward a vision for 21st century food safety assessments. The application of these alternative methods, the need for further development of standardized practices, and the interpretation and communication of results were addressed. Expert presentations encompassed regulatory, industry, and academic perspectives, and the workshop culminated in a panel discussion in which participants engaged experts about current issues pertaining to the application of alternative methods in toxicological testing for food safety assessments.

    更新日期:2019-11-06
  • Residue analysis of gibberellic acid isomer (iso-GA3) in brewing process and its toxicity evaluation in mice
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-06
    Weikang Sun, Chunfeng Liu, Jiaoyang Luo, Chengtuo Niu, Jinjing Wang, Feiyun Zheng, Qi Li

    Gibberellic acid (GA3) is an efficient plant growth regulator, which could speed up barley germination in the brewing industry. However, the residue of GA3 in malt gets denatured into an isomer, termed iso-GA3. In this study, the concentration of iso-GA3 and the conversion rate of GA3 to iso-GA3 during the brewing process was studied by high performance liquid chromatography and the potential toxicity of iso-GA3 was evaluated in ICR mice. The concentration of iso-GA3 increased in the saccharification and wort boiling processes while its concentration was stable during fermentation. The maximum conversion rates of GA3 to iso-GA3 in Canadian malt, Australian malt SCO and Australian malt FAQ were 88%, 87% and 87%, respectively. In the acute oral toxicity study, the median lethal dose (LD50) of iso-GA3 was 2.82 g/kg body weight (BW). In the 28-day repeated dose toxicity study, the iso-GA3 could cause weight loss in mice. And the mice of high-dose group showed a slight decrease in food consumption. Moreover, inflammation and cell necrosis were found in kidney and liver tissue, which were alleviated during the recovery phase. These results establish a practical reference for food safety in products, in which GA3 is added as a food additive.

    更新日期:2019-11-06
  • Subchronic (91–day) oral toxicity study of cellobiose in rats
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-06
    Andreas Winkler, Horst Messinger, Albert Bär
    更新日期:2019-11-06
  • Characteristics of exposure factors and inhalation exposure to selected spray consumer products in Korean population
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-11-04
    Hyerin Shin, Yelim Jang, Miyoung Lim, Ji Young Park, Wonho Yang, Kiyoung Lee

    Many consumer spray products are sold for various purposes. Use of spray products can cause adverse health effects. This study evaluated exposure factors for consumer spray products and assessed the particle inhalation exposure. Six consumer spray products were evaluated: an automobile interior cleaner, car deodorizing spray, anti-static spray, waterproofing spray, microorganism deodorizer, and disinfectant spray. The exposure factors were based on 10,000 respondents over 15 years old. Inhalation dose was calculated from the concentration released into the room air and time used. The use rates of the spray products ranged from 0.4 to 11% and differed significantly by gender (p < 0.001). Aerosol types had a higher mass per use and longer duration of usage than trigger types. The median concentration of the trigger type ranged from 17.35 to 373.38 mg/m3, while that of the aerosol type ranged from 36.66 to 1601.97 mg/m3. The median inhalation dose of the trigger and aerosol types ranged from 2.04 × 10−3 to 0.20 and 2.60 × 10−3 to 1.71 mg/kg/day, respectively. The inhalation dose of the disinfectant spray increased with the level of education (p < 0.001), while the inhalation doses of the other spray products were not significantly associated with gender, age, income, or education.

    更新日期:2019-11-04
  • An FDA analysis of clinical hold deficiencies affecting investigational new drug applications for oncology products
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-31
    Michael L. Manning, Matthew D. Thompson, Haleh Saber, Virginia E. Maher, Joyce Z. Crich, John K. Leighton

    A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of development, product type, sponsors' regulatory experience, and occurrence of a pre-IND meeting. INDs that were placed on hold were mostly for first-in-human trials or submitted by sponsors with limited regulatory experience. INDs that went on hold or were safe-to-proceed had pre-IND meetings with comparable rates but sponsors with substantial experience appeared to benefit more from pre-IND meetings compared to those with limited experience. The time interval between the pre-IND meeting and the IND submission was longer for INDs that went on hold. To obtain useful FDA feedback on product development, it is essential to provide focused questions and supporting information in pre-IND meeting packages.

    更新日期:2019-11-01
  • Development of a prioritization method for chemical-mediated effects on steroidogenesis using an integrated statistical analysis of high-throughput H295R data
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-29
    Derik E. Haggard, Woodrow Setzer, Richard Judson, Katie Paul Friedman

    Synthesis of 11 steroid hormones in human adrenocortical carcinoma cells (H295R) was measured in a high-throughput steroidogenesis assay (HT-H295R) for 656 chemicals in concentration-response as part of the US Environmental Protection Agency's ToxCast program. This work extends previous analysis of the HT-H295R dataset and model by examining the utility of a novel prioritization metric based on the Mahalanobis distance that reduced these 11-dimensional data to 1-dimension via calculation of a mean Mahalanobis distance (mMd) at each chemical concentration screened for all hormone measures available. Herein, we evaluated the robustness of mMd values, and demonstrate that covariance and variance of the hormones measured appear independent of the chemicals screened and are inherent to the assay; the Type I error rate of the mMd method is less than 1%; and, absolute fold changes (up or down) of 1.5 to 2-fold have sufficient power for statistical significance. As a case study, we examined hormone responses for aromatase inhibitors in the HT-H295R assay and found high concordance with other ToxCast assays for known aromatase inhibitors. Finally, we used mMd and other ToxCast cytotoxicity data to demonstrate prioritization of the most selective and active chemicals as candidates for further in vitro or in silico screening.

    更新日期:2019-10-29
  • In vitro and in vivo toxicity evaluation of non-neuroleptic phenothiazines, antitubercular drug candidates
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-28
    Sumayah Salie, Antoinette Labuschagné, Avril Walters, Sohair Geyer, Anwar Jardine, Muazzam Jacobs, Nai-Jen Hsu
    更新日期:2019-10-29
  • Cataracts and statins. A disproportionality analysis using data from VigiBase
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-26
    Diego Macías Saint-Gerons, Francisco Bosco Cortez, Giset Jiménez López, José Luis Castro, Rafael Tabarés-Seisdedos

    The basis of the association between statin use and cataract has been explored using the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase) through January 2019. The reporting odds ratios (RORs) as a measure of disproportionality for reported cataracts and individual statins have been calculated. Subgroup analyses according statin lipophilicity, sex, and age groups have been performed. Moreover, RORs have been calculated for non-statin lipid lowering drugs. An increased disproportionality have been found for most individual statins lovastatin: [ROR: 14.80, 95% confidence interval (CI): 13.30, 16.46)], atorvastatin (ROR: 3.48, 95% CI 3.19–3.80), pravastatin (ROR: 3.15, 95% CI: 2.54–3.90), rosuvastatin (ROR: 2.90, 95% CI: 2.53–3.31), simvastatin (ROR: 2.27, 95%CI: 1.99–2.60), fluvastatin (ROR: 2.03, 95% CI: 1.33–3.08) and statins (overall) ROR: 3.66, 95% CI:3.46–3.86). Increased disproportionality for cataract and statins (drug-class) have been found regardless of statin lipophilicity, sex and group age (more or less than 65 years old). No disproportionality was found for other lipid-lowering drugs (ezetimibe, fibrates or PCSK9 inhibitors). These findings suggest an increased risk of cataract associated with statins as a drug-class. Further studies to characterize the risk are advised. Benefits and potential harms should be considered before starting treatment with statins.

    更新日期:2019-10-27
  • Linking internal dosimetries of the propyl metabolic series in rats and humans using physiologically based pharmacokinetic (PBPK) modeling
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-24
    Jordan N. Smith, Kimberly J. Tyrrell, Jeremy P. Smith, Karl K. Weitz, Willem Faber

    The metabolic series approach has successfully linked internal dosimetries of metabolically related compounds reducing cost and time for chemical risk assessments. Here, we developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the propyl metabolic series including propyl acetate, 1-propanol, propionaldehyde, and propionic acid. Manufacturers use these compounds as organic solvents and intermediates during chemical synthesis. Public exposures can occur through using consumer products containing propyl compounds like cosmetics, aerosol sprays, or foods, and occupational exposures can occur at manufacturing facilities. To develop the PBPK model, we measured in vitro metabolism of propyl acetate in blood and liver S9 fractions. We measured concentrations of propyl compounds in blood following intravenous (iv) infusion of 13C-propanol or 13C-propionic acid and closed chamber inhalation exposures to propyl acetate or propanol in rats. Using these studies and other published data, we modified an existing PBPK model for the butyl metabolic series to simulate time course concentrations of propyl compounds in rats and humans. Consistent with measured in vitro and in vivo data, the optimized propyl series model predicts rapid clearance of propyl acetate, higher concentrations of propanol in blood from propyl acetate inhalation compared to propanol inhalation in rats but not in humans, and low concentrations of propionic acid in blood from exposures to propyl acetate or propanol. Regulators can use this model as a tool for propyl compound risk assessment by linking internal dosimetries under various exposure scenarios.

    更新日期:2019-10-25
  • Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-23
    Adrian Soto-Mota, Hannah Vansant, Rhys D. Evans, Kieran Clarke
    更新日期:2019-10-24
  • Use of benchmark dose models in risk assessment for occupational handlers of eight pesticides used in pome fruit production
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-23
    Jane Gurnick Pouzou, John Kissel, Michael G. Yost, Richard A. Fenske, Alison C. Cullen

    The benchmark dose has been frequently recommended for the creation of points of departure for regulatory dose limits, but many regulations, including pesticide risk assessment and registration in the United States, continues to rely on NOAEL methods as the OECD toxicological standard methods recommend. This study used data from studies in support of pesticide registration for eight different compounds to build dose-response models and calculate benchmark doses and confidence limits. The results were compared to the NOAEL of the same study. A probabilistic estimate of dose was compared with all points of departure to demonstrate differences in the protective ability of each different selected limit. While neither the BMD/BMDL nor the NOAEL was consistently more protective, the advantage of using the BMD in quantifying the uncertainty of the point of departure is highlighted, and the feasibility of using current OECD-guideline studies for derivation of a BMD is demonstrated in these cases.

    更新日期:2019-10-24
  • Quantitative prediction of repeat dose toxicity values using GenRA
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-09-21
    G. Helman, G. Patlewicz, I. Shah

    Computational approaches have recently gained popularity in the field of read-across to automatically fill data-gaps for untested chemicals. Previously, we developed the generalized read-across (GenRA) tool, which utilizes in vitro bioactivity data in conjunction with chemical descriptor information to derive local validity domains to predict hazards observed in in vivo toxicity studies. Here, we modified GenRA to quantitatively predict point of departure (POD) values obtained from US EPA's Toxicity Reference Database (ToxRefDB) version 2.0. To evaluate GenRA predictions, we first aggregated oral Lowest Observed Adverse Effect Levels (LOAEL) for 1,014 chemicals by systemic, developmental, reproductive, and cholinesterase effects. The mean LOAEL values for each chemical were converted to log molar equivalents. Applying GenRA to all chemicals with a minimum Jaccard similarity threshold of 0.05 for Morgan fingerprints and a maximum of 10 nearest neighbors predicted systemic, developmental, reproductive, and cholinesterase inhibition min aggregated LOAEL values with R2 values of 0.23, 0.22, 0.14, and 0.43, respectively. However, when evaluating GenRA locally to clusters of structurally-similar chemicals (containing 2 to 362 chemicals), average R2 values for systemic, developmental, reproductive, and cholinesterase LOAEL predictions improved to 0.73, 0.66, 0.60 and 0.79, respectively. Our findings highlight the complexity of the chemical-toxicity landscape and the importance of identifying local domains where GenRA can be used most effectively for predicting PODs.

    更新日期:2019-10-23
  • Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-09-30
    Vijay Pralhad Kale, Seth Gibbs, John A. Taylor, Amy Zmarowski, Joseph Novak, Kristin Patton, Barney Sparrow, Jenni Gorospe, Satheesh Anand, Resat Cinar, George Kunos, Robert J. Chorvat, Pramod S. Terse

    JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and at 5, 20, and 75 mg/kg/day dose levels for 28 consecutive days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10 mg/kg females and 40 mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40 mg/kg during neurobehavioral testing. Sporadic minimal incidences of decreased activity (males) and seizures (both sexes) were observed in rats during daily clinical observations, without any clear dose-relationship. Male dogs at 75 mg/kg during treatment period, but not recovery period, had an increased incidence of gut associated lymphoid tissue hyperplasia and inflammation in the intestine. In both species, highest dose resulted in lower AUCs indicative of non-linear kinetics. Free access to food increased the plasma AUC∞ by ~4.5-fold at 20 mg/kg in dogs, suggesting presence of food may help in systemic absorption of JD5037 in dogs. Based on the study results, 150 mg/kg/day in rats, and 20 and 75 mg/kg/day doses in male and female dogs, respectively, were determined to be the no-observed-adverse-effect-levels (NOAELs).

    更新日期:2019-10-23
  • Evaluation of preclinical safety profile of SPH3127, a direct renin inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and cynomolgus monkeys
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-01
    Yu Mao, Leduo zhang, Hua Li, Xin Li, Yanjun Liu, Guangxin Xia

    SPH3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable ADME (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase Ι clinical trial. In this work, the subchronic toxicity of SPH3127 in Sprague-Dawley rats and cynomolgus monkeys has been characterized. Rats and monkeys received SPH3127 orally (30, 300, 900 and 20, 100, 450 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days followed by a 28-days recovery period for one third of the animals. The adverse effects of SPH3127 on rats and monkeys mainly included kidney and cardiovascular toxicity, which were consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of renin signaling inhibitors. Moderate liver weight increases accompanied by CYP3A induction were seen in 300 and 900 mg/kg/day rats but not in monkeys or in vitro human hepatocytes. One 450 mg/kg/day monkey died early at day 23 with apparent myelosuppression characterized by atrophy of thymus and spleen, and the relevance to the action of SPH3127 remained unclear. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of SPH3127 was determined to be 30 mg/kg/day for Sprague-Dawley rats and 20 mg/kg/day for cynomolgus monkeys based on the kidney and cardiovascular changes found at mid- and high-dose animals.

    更新日期:2019-10-23
  • Subchronic toxicity evaluation of ethanol extract of Cassia tora L. seeds in rats
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-01
    Mu-Jin Lee, Jong-Hyun Nho, Beo-Deul Yang, Ho Park, Hyun-Joo Lee, Ki-Ho Lee, Ji-Hun Jang, Ho-Kyung Jung, Sun-Ra Kim, Hyun-Woo Cho, Hae-Sung Park, Je-Oh Lim, Jong-Choon Kim
    更新日期:2019-10-23
  • Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-09
    Pranesh Kumar, Aakriti Agarwal, Ashok K. Singh, Anurag Kumar Gautam, Sreemoyee Chakraborti, Umesh Kumar, Dinesh Kumar, Bolay Bhattacharya, Parthasarathi Panda, Biswajit Saha, Tabish Qidwai, Biswanath Maity, Sudipta Saha
    更新日期:2019-10-23
  • Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog®
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-11
    Marcus Korn, Paulus Wohlfart, Thomas Gossas, Mari Kullman-Magnusson, Birgit Niederhaus, Juergen Dedio, Norbert Tennagels

    SAR342434 is a biosimilar of insulin lispro (Humalog® U-100). Batches of SAR342434 were compared with Humalog® batches of either EU or US origin in a panel of in vitro biological assays that included insulin binding to insulin receptor (IR) isoforms A (IR-A) and B (IR-B) and IR-A/IR-B autophosphorylation. A surface plasmon resonance biosensor-based assay was developed to characterize the kinetics of insulin binding to solubilized full-length IR-A or IR-B. Insulin-dependent metabolic activity assays included inhibition of lipolysis in in vitro differentiated human adipocytes, glucose uptake in L6-myocytes, and repression of glucose-6-phosphatase gene expression in human hepatocytes. Mitogenic activity assays included insulin binding to insulin-like growth factor-1 receptor (IGF1R), IGF1R autophosphorylation, and cell proliferation in MCF-7 cells. Weighted geometric means and their respective 95% confidence intervals (CI) were calculated for all 50% inhibitory or effective concentration values and kinetic binding constants for IR-A and IR-B. Statistical evaluation of the data demonstrated that the 90% CIs of the ratio of geometric means between SAR342434 and Humalog® EU or Humalog® US were within the predefined acceptance limits for each assay. Insulin lispro as SAR342434 solution demonstrated similarity to both US- and EU-approved Humalog® based on a side-by-side biological similarity assessment.

    更新日期:2019-10-23
  • Toxicological significance of increased serum alkaline phosphatase activity in dog studies of pesticides: Analysis of toxicological data evaluated in Japan
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-09-27
    Yoko Yokoyama, Atsushi Ono, Midori Yoshida, Kiyoshi Matsumoto, Mikako Saito

    Increased serum alkaline phosphatase (ALP) activity is an indicator of hepatobiliary damage in humans and experimental animals. Practically, increased ALP accompanied by no other hepatotoxic changes is often encountered in toxicity studies of pesticides in dogs. Here, we analyzed the toxicological significance of increased ALP in response to 206 pesticides evaluated by the Food Safety Commission of Japan as toxicological evaluation reports in their risk assessment process. Our analysis indicated that increased ALP was more frequent in dogs (108/206) than in rats (36/206). In 87 of 108 pesticides, increased ALP was observed with hepatotoxicity in dogs. However, increased ALP had no specific relationship with certain types of hepatotoxicity and was not a sensitive marker of hepatotoxicity. Approximately 50% of 87 pesticides showing hepatotoxicity also induced liver hypertrophy. No hepatotoxic changes were seen with the remaining 21 pesticides, other than increases in liver weight and/or liver hypertrophy. Most of these 21 pesticides were phenobarbital-like liver metabolism enzyme inducers in rodents. These results suggested that increased ALP was not an indicator of hepatotoxicity in dogs if hepatotoxic findings were absent. This analysis provided a new interpretation of the toxicological significance of ALP in dogs and could contribute to toxicological evaluation of pesticides.

    更新日期:2019-10-23
  • Tetrahydrofuran-induced tumors in rodents are not relevant to humans: Quantitative weight of evidence analysis of mode of action information does not support classification of tetrahydrofuran as a possible human carcinogen
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-15
    Wolfgang Dekant

    Inhalation of tetrahydrofuran (THF) causes a marginal increase in the incidence of renal tumors in male rats and an increase in the incidence of liver tumors in female mice. Quantitative weight of evidence (QWoE) was applied to assess experimental support for biologically plausible modes of action (MoA) of tumor formation by THF and their human relevance. QWoE did not obtain support for a MoA to induce kidney tumors in male rats from THF exposure via α2u -globulin nephropathy, exacerbation of chronic progressive nephropathy (CPN), DNA-damage, or recurrent cytotoxicity but obtained moderate to good support for a constitutive androgen receptor (CAR)-mediated MoA for the induction of liver tumors in female mice. Tumors as a consequence of CAR-activation are not considered relevant to humans. Considering the previous conclusion that the increases in kidney tumors in male rats are unlikely related to THF-exposure and the support for a CAR-mediated MoA in mice obtained here, these tumors should not be used as a basis for THF cancer classification.

    更新日期:2019-10-23
  • Pulmonary toxicity in rats following inhalation exposure to poorly soluble particles: The issue of impaired clearance and the relevance for human health hazard and risk assessment
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-08
    Peter M.J. Bos, Ilse Gosens, Liesbeth Geraets, Christiaan Delmaar, Flemming R. Cassee

    Intensive discussions are ongoing about the interpretation of pulmonary effects observed in rats exposed to poorly soluble particles. Alveolar clearance differs between rats and humans and becomes impaired in rats at higher exposure concentrations. Some have doubted the human relevance of toxic effects observed in rats under impaired clearance conditions and have suggested that experimental exposures should stay below concentrations inducing impaired clearance. However, for regulatory purposes, insight in potential health effects at relatively high concentrations is needed to fully understand the hazard. Many aspects of impaired particle clearance remain unclear, hampering human health hazard and risk assessment. For an adequate evaluation of the impact of impaired clearance on pulmonary toxicity, a clear definition of alveolar clearance is needed that enables to quantitatively relate the level of impairment to the induction of adverse pulmonary health effects. Also, information is needed on the mechanism of action and the appropriate dose metric for the pulmonary effects observed. In absence of these data, human hazard and risk assessment can only be performed in a pragmatic way. Unless available data clearly point out otherwise, rat pulmonary toxicity including lung inflammation and tumour formation, needs to be considered relevant for human hazard and risk assessment.

    更新日期:2019-10-23
  • Transitioning to composite bacterial mutagenicity models in ICH M7 (Q)SAR analyses
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-03
    Curran Landry, Marlene T. Kim, Naomi L. Kruhlak, Kevin P. Cross, Roustem Saiakhov, Suman Chakravarti, Lidiya Stavitskaya

    The International Council on Harmonisation (ICH) M7(R1) guideline describes the use of complementary (quantitative) structure-activity relationship ((Q)SAR) models to assess the mutagenic potential of drug impurities in new and generic drugs. Historically, the CASE Ultra and Leadscope software platforms used two different statistical-based models to predict mutations at G-C (guanine-cytosine) and A-T (adenine-thymine) sites, to comprehensively assess bacterial mutagenesis. In the present study, composite bacterial mutagenicity models covering multiple mutation types were developed. These new models contain more than double the number of chemicals (n = 9,254 and n = 13,514) than the corresponding non-composite models and show better toxicophore coverage. Additionally, the use of a single composite bacterial mutagenicity model simplifies impurity analysis in an ICH M7 (Q)SAR workflow by reducing the number of model outputs requiring review. An external validation set of 388 drug impurities representing proprietary pharmaceutical chemical space showed performance statistics ranging from of 66–82% in sensitivity, 91–95% in negative predictivity and 96% in coverage. This effort represents a major enhancement to these (Q)SAR models and their use under ICH M7(R1), leading to improved patient safety through greater predictive accuracy, applicability, and efficiency when assessing the bacterial mutagenic potential of drug impurities.

    更新日期:2019-10-23
  • Applying non-animal strategies for assessing skin sensitisation report from an EPAA/cefic-LRI/IFRA Europe cross sector workshop, ECHA helsinki, February 7th and 8th 2019
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-03
    David Basketter, Philippe Azam, Silvia Casati, Marco Corvaro, Janine Ezendam, Peter Griem, Bruno Hubesch, Amaia Irizar, Petra Kern, Irene Manou, Annette Mehling, Laura H. Rossi

    Four years on since the last cross sector workshop, experience of the practical application and interpretation of several non-animal assays that contribute to the predictive identification of skin sensitisers has begun to accumulate. Non-animal methods used for hazard assessments increasingly are contributing to the potency sub-categorisation for regulatory purposes. However, workshop participants generally supported the view that there remained a pressing need to build confidence in how information from multiple methods can be combined for classification, sub-categorisation and potency assessment. Furthermore, the practical experience gained over the last few years, highlighted the overall high potential value of using the newly validated methods and testing strategies, but also that limitations for certain substance/product classes may become evident with further use as had been the case with other new regulatory methods. As the available information increases, review of the data and collated experience could further determine strengths and limitations leading to more confidence in their use. Finally, the need for a substantial and universally accepted dataset of non-sensitisers and substances of different sensitising potencies, based on combined human and in vivo animal data for validation of methods and test strategies was re-emphasised.

    更新日期:2019-10-23
  • Evaluating potential refinements to existing Threshold of Toxicological Concern (TTC) values for environmentally-relevant compounds
    Regul. Toxicol. Pharmacol. (IF 2.996) Pub Date : 2019-10-19
    Mark D. Nelms, Prachi Pradeep, Grace Patlewicz

    The Toxic Substances Control Act (TSCA) mandates the US EPA perform risk-based prioritisation of chemicals in commerce and then, for high-priority substances, develop risk evaluations that integrate toxicity data with exposure information. One approach being considered for data poor chemicals is the Threshold of Toxicological Concern (TTC). Here, TTC values derived using oral (sub)chronic No Observable (Adverse) Effect Level (NO(A)EL) data from the EPA's Toxicity Values database (ToxValDB) were compared with published TTC values from Munro et al. (1996). A total of 4554 chemicals with structures present in ToxValDB were assigned into their respective TTC categories using the Toxtree software tool, of which toxicity data was available for 1304 substances. The TTC values derived from ToxValDB were similar, but not identical to the Munro TTC values: Cramer I ((ToxValDB) 37.3 c. f. (Munro) 30 μg/kg-day), Cramer II (34.6 c. f. 9.1 μg/kg-day) and Cramer III (3.9 c. f. 1.5 μg/kg-day). Cramer III 5th percentile values were found to be statistically different. Chemical features of the two Cramer III datasets were evaluated to account for the differences. TTC values derived from this expanded dataset substantiated the original TTC values, reaffirming the utility of TTC as a promising tool in a risk-based prioritisation approach.

    更新日期:2019-10-23
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