基准剂量法在电焊工人尿锰含量与血清过氧化氢酶活性关联研究中的应用

目的：利用基准剂量（BMD）法探讨电焊工人尿锰含量对血清过氧化氢酶（CAT）活性的影响.方法：对广州市某造船厂78例电焊工人尿锰含量和血清CAT活性进行测定,按照尿锰含量的不同分为4组：≤0.03 mg/L、〉0.03 mg/L～0.05 mg/L、〉0.05 mg/L～0.07 mg/L和〉0.07 mg/L,分析尿锰含量和血清CAT活性之间的关系.根据血清CAT活性的变化判断尿锰含量的正常参考值,计算各组血清CAT活性异常率.采用美国环境保护署（EPA）的BMDS软件,计算电焊工人尿锰含量的BMD和基准剂量下限（BMDL）.结果：不同尿锰含量组血清CAT活性水平和CAT活性异常率差异无统计学意义（均P〉0.05）.电焊工人尿锰含量的BMD及BMDL分别为0.081 0 mg/L和0.0013 mg/L.结论：电焊作业者尿锰含量高于0.081 0 mg/L可能引起血清CAT活性下降.     

State of the art in benefit-risk analysis: Food and nutrition

Benefit-risk assessment in food and nutrition is relatively new. It weighs the beneficial and adverse effects that a food (component) may have, in order to facilitate more informed management decisions regarding public health issues. It is rooted in the recognition that good food and nutrition can improve health and that some risk may be acceptable if benefit is expected to outweigh it. This paper presents an overview of current concepts and practices in benefit-risk analysis for food and nutrition. It aims to facilitate scientists and policy makers in performing, interpreting and evaluating benefit-risk assessments.Historically, the assessments of risks and benefits have been separate processes. Risk assessment is mainly addressed by toxicology, as demanded by regulation. It traditionally assumes that a maximum safe dose can be determined from experimental studies (usually in animals) and that applying appropriate uncertainty factors then defines the ‘safe’ intake for human populations. There is a minor role for other research traditions in risk assessment, such as epidemiology, which quantifies associations between determinants and health effects in humans. These effects can be both adverse and beneficial. Benefit assessment is newly developing in regulatory terms, but has been the subject of research for a long time within nutrition and epidemiology. The exact scope is yet to be defined. Reductions in risk can be termed benefits, but also states rising above ‘the average health’ are explored as benefits. In nutrition, current interest is in ‘optimal’ intake; from a population perspective, but also from a more individualised perspective.In current approaches to combine benefit and risk assessment, benefit assessment mirrors the traditional risk assessment paradigm of hazard identification, hazard characterization, exposure assessment and risk characterization. Benefit-risk comparison can be qualitative and quantitative. In a quantitative comparison, benefits and risks are expressed in a common currency, for which the input may be deterministic or (increasingly more) probabilistic. A tiered approach is advocated, as this allows for transparency, an early stop in the analysis and interim interaction with the decision-maker. A general problem in the disciplines underlying benefit-risk assessment is that good dose-response data, i.e. at relevant intake levels and suitable for the target population, are scarce.It is concluded that, provided it is clearly explained, benefit-risk assessment is a valuable approach to systematically show current knowledge and its gaps and to transparently provide the best possible science-based answer to complicated questions with a large potential impact on public health.     

Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat

This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were compared with those of a previously developed PBK model for methyleugenol (ME) in male rat. The results obtained reveal that formation of 1′-hydroxymethyleugenol glucuronide (1′HMEG), a major metabolic pathway in male rat liver, appears to represent a minor metabolic pathway in human liver whereas in human liver a significantly higher formation of 1′-oxomethyleugenol (1′OME) compared with male rat liver is observed. Furthermore, formation of 1′-sulfooxymethyleugenol (1′HMES), which readily undergoes desulfonation to a reactive carbonium ion (CA) that can form DNA or protein adducts (DA), is predicted to be the same in the liver of both human and male rat at oral doses of 0.0034 and 300 mg/kg bw. Altogether despite a significant difference in especially the metabolic pathways of the proximate carcinogenic metabolite 1′-hydroxymethyleugenol (1′HME) between human and male rat, the influence of species differences on the ultimate overall bioactivation of methyleugenol (ME) to 1′-sulfooxymethyleugenol (1′HMES) appears to be negligible. Moreover, the PBK model predicted the formation of 1′-sulfooxymethyleugenol (1′HMES) in the liver of human and rat to be linear from doses as high as the benchmark dose (BMD₁₀) down to as low as the virtual safe dose (VSD). This study shows that kinetic data do not provide a reason to argue against linear extrapolation from the rat tumor data to the human situation.     

Red cell transfusion in orthopaedic surgery: a benchmark study performed combining data from different data sources

Background

Previous studies have shown the usefulness of combining information from different data sources to identify and analyse variations in transfusion practices. Good knowledge of the conditions leading to blood use is a fundamental requirement for the assessment of the appropriateness of blood transfusion.

Materials and methods

In this study we combined blood transfusion data obtained from the Blood Bank information system with patients’ data from the Hospital Discharge Database, based on the ICD9 classification system, from 1,827 surgical procedures performed in seven different orthopaedic divisions in the Ravenna area between January and December 2009. Hip and knee replacement surgery (primary or revision) and operations following femoral fractures (partial hip replacement and reduction with internal fixation) were considered. For a subgroup of patients clinical and transfusion data were also combined with haemoglobin values obtained from the laboratory information system.

Results

Of the 1,827 surgical procedures, 1,038 (56.8%) were followed by transfusion of red cells. The likelihood of receiving a transfusion varied depending on the patient’s sex (49% for males, 60% for females), age, and on the surgical procedure, being higher for interventions following femoral fractures and for revisions of hip replacement: about 70% of patients undergoing these interventions required transfusion. A large variability in transfusion rates was observed between the seven divisions, which was only partially explained by the different types of surgery (post-traumatic or elective) performed by any of them: relevant variations were also observed for the same type of intervention.

Discussion

Combining information from different data sources could be a time-sparing way to gain useful information about transfusion practices, so contributing to optimising blood usage.     

Approaches to cancer assessment in EPA's Integrated Risk Information System

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) Program develops assessments of health effects that may result from chronic exposure to chemicals in the environment. The IRIS database contains more than 540 assessments. When supported by available data, IRIS assessments provide quantitative analyses of carcinogenic effects. Since publication of EPA's 2005 Guidelines for Carcinogen Risk Assessment, IRIS cancer assessments have implemented new approaches recommended in these guidelines and expanded the use of complex scientific methods to perform quantitative dose-response assessments. Two case studies of the application of the mode of action framework from the 2005 Cancer Guidelines are presented in this paper. The first is a case study of 1,2,3-trichloropropane, as an example of a chemical with a mutagenic mode of carcinogenic action thus warranting the application of age-dependent adjustment factors for early-life exposure; the second is a case study of ethylene glycol monobutyl ether, as an example of a chemical with a carcinogenic action consistent with a nonlinear extrapolation approach. The use of physiologically based pharmacokinetic (PBPK) modeling to quantify interindividual variability and account for human parameter uncertainty as part of a quantitative cancer assessment is illustrated using a case study involving probabilistic PBPK modeling for dichloromethane. We also discuss statistical issues in assessing trends and model fit for tumor dose-response data, analysis of the combined risk from multiple types of tumors, and application of life-table methods for using human data to derive cancer risk estimates. These issues reflect the complexity and challenges faced in assessing the carcinogenic risks from exposure to environmental chemicals, and provide a view of the current trends in IRIS carcinogenicity risk assessment.     

Evaluation of research activities and research needs to increase the impact and applicability of alternative testing strategies in risk assessment practice

The present paper aims at identifying strategies to increase the impact and applicability of alternative testing strategies in risk assessment. To this end, a quantitative and qualitative literature evaluation was performed on (a) current research efforts in the development of in vitro methods aiming for alternatives to animal testing, (b) the possibilities and limitations of in vitro methods for regulatory purposes and (c) the potential of physiologically-based kinetic (PBK) modeling to improve the impact and applicability of in vitro methods in risk assessment practice. Overall, the evaluation showed that the focus of state-of-the-art research activities does not seem to be optimally directed at developing in vitro alternatives for those endpoints that are most animal-demanding, such as reproductive and developmental toxicity, and carcinogenicity. A key limitation in the application of in vitro alternatives to such systemic endpoints is that in vitro methods do not provide so-called points of departure, necessary for regulators to set safe exposure limits. PBK-modeling could contribute to overcoming this limitation by providing a method that allows extrapolation of in vitro concentration-response curves to in vivo dose-response curves. However, more proofs of principle are required.     

A novel application of the Margin of Exposure approach: Segregation of tobacco smoke toxicants

This paper presents a rationale for utilising a Margin of Exposure (MOE) approach to the segregation of tobacco smoke toxicants for risk assessment and management purposes. Future regulatory frameworks and product modifications aimed at tobacco harm reduction could utilise data that segregate toxicants using associations with specific diseases caused by cigarette smoking together with an indication of their relative contribution to that disease. Compounds with MOEs >10,000 accompanied by appropriate narrative are considered “low priority for risk management actions”. This paper applies the MOE model to representative examples of tobacco smoke toxicants associated with respiratory tract carcinogenesis and other respiratory diseases. A multiplicity of published dose response data on individual toxicants has been used to determine the range of possible MOE values, thus demonstrating the consistency of the relationships. Acetaldehyde, acrolein, acrylonitrile, cadmium, ethylene oxide, formaldehyde and isoprene all segregate with MOEs <10,000 and should be considered as high priority for exposure reduction research whereas benzo(a)pyrene and vinyl chloride segregate with an MOE >10,000 and therefore may be considered as a low priority. 1,3-Butadiene, m-/p-cresols, NNK and NNN are assumed to segregate with high priority although additional data would be required to complete a full MOE assessment.     

Relative developmental toxicity potencies of retinoids in the embryonic stem cell test compared with their relative potencies in in vivo and two other in vitro assays for developmental toxicity

The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds.     

In utero and lactational exposure to Aroclor 1254 affects bone geometry, mineral density and biomechanical properties of rat offspring

Exposure to polychlorinated biphenyls (PCBs) induce a broad spectrum of toxic effects in various organs including bone. The most susceptible age-groups to the toxic effects of PCBs are foetuses and infants. The aim of the present study was to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following perinatal exposure to the PCB mixture, Aroclor 1254 (A1254), and to examine the persistence of observed bone alterations by following the offspring over time. Sprague-Dawley rat offspring were exposed to A1254 from gestational day 1 to post-natal day (PND) 23. Femur and tibia were collected on PNDs 35, 77 and 350 and were analyzed by peripheral quantitative computed tomography and biomechanical testing. At PND35, exposure to A1254 induced short, thin femur and tibia, with reduced mechanical strength of femoral neck. No treatment-related bone changes were detected in offspring at PND77 or PND350. In conclusion, the present investigation suggests that perinatal exposure to A1254 leads to shorter, thinner and weaker bones in juvenile rats at PND35, with these effects being absent at later time-points as exposure is discontinued. The results indicate that the observed bone effects are mainly driven by the dioxin-like congeners, although it cannot exclude the contribution of the non dioxin-like congeners to the exposure outcome.     

A method to determine precise benchmark doses for carbamate anticholinesterases.

In determining benchmark doses for risk assessment and regulation of carbamate anticholinesterase pesticides like formetanate, oxamyl, and methomyl, one needs to quantitate low levels of cholinesterase inhibition. For improved accuracy while using fewer subjects, we developed an assay based on the recognized ability of carbamates to protect cholinesterase from irreversible inactivation. This assay measures enzyme that survives diisopropylfluorophosphate exposure in vitro and then reactivates by decarbamylation after small molecules are removed with size-exclusion centrifugation. The 99% silencing of unprotected cholinesterase yields a low background. Comparisons of recovered activity with initial activity (representing carbamate-free enzyme) use each sample as its own control. As a result, carbamate-protection assays can demonstrate a statistically significant 2-3% inhibition of brain cholinesterase in a single experimental group of modest size. When applied to brain samples from formetanate-treated rats, such an assay predicted a benchmark dose of 0.19 mg/kg for 10% inhibition (BMD10), with a lower 95% confidence limit of 0.15 mg/kg (BMDL10). Protection assays should enable precise determinations of benchmark doses for other carbamates, as well as accurate assessment of in vivo inhibition half-lives under low-dose scenarios.