Proposal for a revised Reference Concentration (RfC) for manganese based on recent epidemiological studies

In 1993, based on observations of subclinical neurological effects in workers, the United States Environmental Protection Agency (US EPA) published a Reference Concentration (RfC) of 0.05 μg/m³ for manganese (Mn). The geometric mean exposure concentration, 150 μg/m³ respirable Mn, was considered the lowest observable adverse effect level (LOAEL), and uncertainty factors (UFs) were applied to account for sensitive populations, database limitations, a LOAEL, subchronic exposure, and potential differences in toxicity of different forms of Mn. Based on a review of more recent literature, we propose two alternate Mn RfCs. Of 12 more recent occupational studies of eight cohorts with chronic exposure durations, examining subclinical neurobehavioral effects, predominantly on the motor system, three were considered appropriate for development of an RfC. All three studies yielded no observable adverse effect levels (NOAELs) of approximately 60 μg/m³ respirable Mn. Converting the occupational NOAEL to a human equivalent concentration (HEC) of 21 μg/m³ (for continuous exposure) and applying a UF of 10 to account for intraspecies variability yielded an RfC of 2 μg/m³. We also derived a similar RfC (7 μg/m³) using an Mn benchmark dose (BMD) as the point of departure. Overall confidence in both RfCs is medium.     

Proposal for reference concentrations (RfC) for inhalation exposure to methanol

A tentative reference concentration (RfC) for methanol in ambient air, i.e. an exposure concentration below which adverse effects are not expected to occur, was derived from the analysis of the toxicological data available in the literature. Well-documented studies that correlate environmental levels of methanol with observed toxic effects have not been found in the literature, nor have any long-term epidemiological studies of chronic low-level occupational exposure been found. Assessment of RfC for acute inhalation exposure is based on a human study (n=26 subjects) with a 'tentative' NOAEL of 262 mg/m(3). The calculated RfC for 1 h exposure is 104.8 mg/m(3). The RfC is given a low confidence rating as there was only one methanol concentration used. A well designed study on monkeys served as the basis for the assessment of RfC for chronic inhalation exposure. In this study, 13.1 and 131 mg/m(3) were considered as NOAEL and LOAEL, respectively. The calculated RfC is 0.38 mg/m(3). The overall database is weak, lacking data on reproductive and developmental endpoints in human or non-human primates. Nevertheless, the RfC is given a medium confidence rating because of the strength of the principal study.     

Application of a Physiologically Based Pharmacokinetic Model for Reference Dose and Reference Concentration Estimation for Acetone

Recent health risk assessments to propose a Reference Dose (RfD) for acetone (Forsyth, 2001; U.S. EPA, 2001) have been based on the results of an oral subchronic study conducted in rats and mice (Dietz et al., 1991; NTP, 1991). These assessments have utilized the traditional concept of establishing the RfD by determining the lowest experimentally determined No-Observed-Adverse-Effect Level (NOAEL) and applying various Uncertainty Factors (UFs) (U.S. EPA, 1988). This article describes a risk assessment for acetone based on the systemic toxicity observed in subchronic and developmental toxicity studies to estimate an RfD and an inhalation reference concentration (RfC) for acetone. Specifically, this approach examined the subchronic study by Dietz et al. (1991), as well as an inhalation developmental toxicity study on acetone (Mast et al., 1988) and several toxicology studies of isopropanol (IPA). This was accomplished by applying a physiologically based pharmacokinetic (PBPK) model developed previously for IPA and its metabolite acetone (Clewell et al., 2001). The incorporation of the PBPK model into the derivation of an RfD and RfC for acetone allowed for a tissue-based approach rather than an external exposure-based approach, making it possible to derive an oral RfD from an inhalation study. In addition, the use of the PBPK model to analyze data from chronic and reproductive/developmental studies conducted with IPA enabled an assessment of the potential for acetone to produce any of the effects observed in the IPA studies. This analysis provided sufficient information to reduce the need for UFs in the adjustment of the NOAEL from the oral subchronic study for the determination of an RfD. Using the PBPK model in the acetone risk assessment supports a composite UF of 60 for the subchronic study, compared to composite factors of 300 to 3000 in the other recent risk assessments. This difference resulted in an RfD of 16 mg/kg/d, compared to the values of 0.3 to 3 that have previously been estimated (Forsyth, 2001; U.S. EPA, 2001). Considering the results from the inhalation developmental study (Mast et al., 1988) resulted in an RfD of 8.7 mg/kg/d. Using this study also fills a data gap for acetone that exists if only the oral database for acetone is considered for RfD derivation. An RfC of 29ppm was also estimated for acetone using the Mast et al. (1988) study results in combination with the PBPK model. The potential impact of endogenous acetone on a risk assessment for acetone is also discussed.     

Timely awareness and prevention of emerging chemical and biochemical risks in foods: Proposal for a strategy based on experience with recent cases

A number of recent food safety incidents have involved chemical substances, while various activities aim at the early identification of emerging chemical risks. This review considers recent cases of chemical and biochemical risks, as a basis for recommendations for awareness and prevention of similar risks at an early stage. These cases include examples of unapproved genetically modified food crops, intoxications with botanical products containing unintentionally admixed toxic herbs, residues of unapproved antibiotics and contaminants in farmed aquaculture species such as shrimp and salmon; and adverse effects of chemical and biological pesticides of natural origin. Besides case-specific recommendations for mitigation of future incidents of the same nature, general inferences and recommendations are made. It is recommended, for example, to establish databases for contaminants potentially present within products. Pro-active reconnaissance can facilitate the identification of products potentially contaminated with hazardous substances. In international trade, prevention and early identification of hazards are aided by management systems for product quality and safety, rigorous legislation, and inspections of consignments destined for export. Cooperation with the private sector and foreign authorities may be required to achieve these goals. While food and feed safety are viewed from the European perspective, the outcomes also apply to other regions.     

Initial reliability and validity studies of the revised Treatment Services Review (TSR-6)

OBJECTIVE: Report the results of initial reliability and validity analyses for a revised Treatment Services Review (TSR-6) instrument which measures a broader range of services than the original TSR. METHOD: First, the number of services for a 28-day period was compared for three versions of the instrument varying in their reporting timeframes. Accordingly, four successive 7-day TSR-6s, two 14-day TSR-6s, or one 28-day TSR-6 were administered to more than 300 clients (30% women) in substance abuse treatment (SAT). Second, short-term (2-5 days) test-retest reliabilities were compared for an initial 7-, 14-, or 28-day version of the TSR-6. Third, test-retest reliabilities were compared when an initial in-person (IP) administration was followed by either IP or telephone (TEL) TSR-6 administration. Finally, preliminary discriminative validity analyses were conducted. RESULTS: Few differences in the quantity of services reported for a 4-week period were found with versions of the TSR-6 that used different timeframes. Also, comparisons of test-retest reliabilities for the different version of the TSR-6 revealed few differences. Test-retest reliabilities were generally comparable for the IP-TEL and IP-IP conditions. Finally, analyses demonstrated preliminary discriminative validity for the instrument when services for three distinctive forms of treatment: intensive outpatient, methadone and residential were compared. CONCLUSIONS: The findings of this study support the reliability and validity of the TSR-6 and suggest that a version with a 28-day reporting period can provide information comparable to that obtained with versions using shorter reporting periods.     

Estimation of human maximum tolerable intake for methylmercury based on two recent studies in monkeys

Results of long-term toxicity studies of methylmercury (MeHg) in monkeys have been reported. The aim of this study was to estimate the threshold body burden, blood level and threshold daily intake (TDI) of MeHg for monkey and human. The concepts of this study stood on that body burden of MeHg would follow the accumulation theory, and that the more intake of MeHg, the earlier the neurotoxicity appeared, vice versa. The threshold blood level (TBL) of monkey was estimated to be 0.71 as Hg mg/L and the body burden was estimated to be 4.83 as Hg mg/kg. The TDI was estimated to be 0.025 as Hg mg/kg day. In human, the TBL was estimated with compensation by elimination constants of human and monkey. The blood threshold limit and TDI of human were estimated to be 0.33 as Hg mg/L and 0.0046 as Hg mg/kg day, respectively. The estimated body burden was 0.46 as Hg mg/kg.     

Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data

In this paper, we propose a quantitative risk assessment methodology for skin sensitization aiming at the derivation of 'safe' exposure levels for sensitizing chemicals, used e.g., as ingredients in consumer products. Given the limited number of sensitizers tested in human sensitization tests, such as the human repeat-insult patch test (HRIPT) or the human maximization test (HMT), we used EC3 values from the local lymph node assay (LLNA) in mice because they provide the best quantitative measure of the skin sensitizing potency of a chemical. A comparison of LLNA EC3 values with HRIPT and HMT LOEL, and NOEL values was carried out and revealed that the EC3, expressed as area dose, can be used as a surrogate value for the human NOEL in risk assessment. The uncertainty/extrapolation factor approach was used to derive (a) an 'acceptable non-sensitizing area dose' (ANSAD) to protect non-allergic individuals against skin sensitization and (b) an 'acceptable non-eliciting area dose' (ANEAD) to protect allergic individuals against elicitation of allergic contact dermatitis. For ANSAD derivation, interspecies, intraspecies and time extrapolation factors are applied to the LLNA EC3. For ANEAD derivation, additional application of a variable sensitization-elicitation extrapolation factor is proposed. Values for extrapolation factors are derived and discussed, the proposed methodology is applied to the sensitizers methylchloroisothiazolinone/methylisothiazolinone, cinnamic aldehyde and nickel and results are compared to published risk assessments.     

Drug use in pregnancy: an overview of epidemiological (drug utilization) studies

Summary The need for further information on drug utilization patterns during pregnancy in different countries was assessed by reviewing literature obtained by hand and computer searches for the years 1960–1988.The 13 identified studies showed that pregnant women used an average of 4.7 drugs. The most commonly ingested medications were vitamins and iron preparations (almost all women), analgesics, antiemetics and antacids.However, the important variables taken into account differently in each study, such as date of surveillance, country, size of population, personal habits, and physiopathological and demographic characteristics, may it impossible to construct a comprehensive, detailed, up-to-date picture of drug utilization during pregnancy.The evaluation confirmed the need for systematic permanent surveillance of drug utilization in pregnancy, so as to avoid the use of data based on widely differing contexts, times and methods, in a field where knowledge is often derived from scanty information.This study was supported in part by the National Research Council (CNR, Rome, Italy), Convenzione Farmacologia Clinica     

Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.     

注射类药物应表述等渗浓度稀释量和静注最大浓度参考的意见

中国药品标准编辑部： 因贵刊旨在服务于药品标准事宜，所以是中国药典、药理学和药物学的进一步诠释者和其药品政策与法规的说明者、代言者。因此笔者对注射类药物的说明书提两点补充意见供参考，并希望能得到指正。     

Proposal for a risk banding framework for inhaled low aspect ratio nanoparticles based on physicochemical properties

We present a conceptual framework that can be used to assign risk bands to inhaled low aspect ratio nanoparticles starting from exposure bands assigned to a specific exposure situation. The framework mimics a basic physiological scheme that captures the essential mechanisms of fate and toxicity of inhaled nanoparticles and is composed of several models and rules that estimate the result of the following processes: the deposition of particles in the respiratory tract, their (de-)agglomeration, lung burden and clearance, their diffusion through the lung mucus layer, translocation and cellular uptake and local and systemic toxicity. Each model is based on a set of particle’s physicochemical properties, including the size and size distribution(s), the zeta potential (or net charge at a specific pH), the surface hydrophobicity or hydrophilicity, the conduction band energy (for metals, metal oxides, quantum dots, etc.) and the solubility at a specific pH. The framework takes the exposure bands as input and predicts, using the above-mentioned models, an internal dose band (module 1). Module 2 assigns a relative hazard ranking depending on the region of particle deposition in the respiratory tract, the likelihood of uptake and whether the toxicological effects are assumed to be local and/or systemic. By combining the results of Module 1 and 2, the framework provides a relative risk ranking.     

Proposal for a basic law of neural communication: response = a(stimulus)(0.5) + b

A basic law of neural communication is proposed to be: response = a(stimulus)(0.5) + b, whether referring to operation of a particular nervous system as a whole or to portions thereof, from receptors to effectors. This differs from previous formulations in that the exponent is set at a constant value of 0.5 rather than being considered to vary from one instance to another. Supporting data is presented.     

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014–2017) and perspectives

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of ‘integrated pharmacokinetics of TCMs’ from 2014 to 2017 and the part of ‘reverse pharmacokinetics in drug discovery from natural medicines’ in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb–drug interactions and herb–herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.     

HPLC method validation studies on a specific assay for monomethoxypoly(ethylene glycol) succinimido carbonate (mPEG-SC)

An UV-HPLC method for the determination of the potency of mPEG-SC, 5 kDa (1) has been developed and validated. Validation acceptance criteria that is typical of small molecule method validation was successfully applied for this method. The method relies on the HPLC separation of mPEG-OH, 5 kDa (2) and a derivatized form of mPEG-SC, 5 kDa (1). 1-Naphthylmethylamine reacts with mPEG-SC, 5 kDa (1) to form a stable, strongly UV absorbing carbamate 3. When the eluent is analyzed by UV detection at 220 nm, the method was shown to be linear, precise and accurate. The limit of detection of the method was 0.1 μg.     

Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review and revise its first (2006) Guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A to D, with A having the strongest evidence base (from randomized controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and brain imaging can improve diagnostic accuracy (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for mild to moderate Alzheimer's disease (A) and memantine for moderate to severe Alzheimer's disease (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), especially for neuropsychiatric symptoms (A). Cholinesterase inhibitors and memantine can produce cognitive improvements in DLB (A). There is no clear evidence that any intervention can prevent or delay the onset of dementia. Although the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition are in progress. Although results of pivotal studies are awaited, results to date have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use.     

Nonclinical studies and clinical studies on fosfluconazole, a triazole antifungal agent (Prodif)

Fosfluconazole is a phosphate prodrug of fluconazole that has been developed to reduce the volume of fluid required to administer fluconazole by the intravenous route. Fosfluconazole is hydrolyzed by alkaline phosphatase to fluconazole and phosphoric acid. Fosfluconazole had no significant antifungal activity in vitro. However, in rat models of acute systemic candidiasis and intracranial cryptococcosis, fosfluconazole retained the antifungal potency and efficacy of fluconazole. This reflects the effective conversion of the prodrug to the parent during the course of the experiments. The 2-day-loading dose regimen led to earlier achievement of target fluconazole steady state plasma concentrations compared to use of the 1-day- or no-loading dose regimen of fosfluconazole. The efficacy and safety of fosfluconazole were investigated with the 2-day-loading dose regimen in patients with deep-seated mycosis caused by Candida and Cryptococcus species. The efficacy rates were 73.8% in the domestic Phase III study and 91.7% in the foreign Phase III study. Adverse events were observed in 31 cases (19.4%) out of 160 in both studies. These results indicate that fosfluconazole is effective for the treatment of deep-seated mycosis and shows no clinically significant adverse events in the Phase III studies