Role of biomarkers in monitoring exposures to chemicals: present position,future prospects

Biomarkers are becoming increasingly important in toxicology and human health. Many research groups are carrying out studies to develop biomarkers of exposure to chemicals and apply these for human monitoring. There is considerable interest in the use and application of biomarkers to identify the nature and amounts of chemical exposures in occupational and environmental situations. Major research goals are to develop and validate biomarkers that reflect specific exposures and permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This review presents a commentary and consensus views about the major developments on biomarkers for monitoring human exposure to chemicals. A particular emphasis is on monitoring exposures to carcinogens. Significant developments in the areas of new and existing biomarkers, analytical methodologies, validation studies and field trials together with auditing and quality assessment of data are discussed. New developments in the relatively young field of toxicogenomics possibly leading to the identification of individual susceptibility to both cancer and non-cancer endpoints are also considered. The construction and development of reliable databases that integrate information from genomic and proteomic research programmes should offer a promising future for the application of these technologies in the prediction of risks and prevention of diseases related to chemical exposures. Currently adducts of chemicals with macromolecules are important and useful biomarkers especially for certain individual chemicals where there are incidences of occupational exposure. For monitoring exposure to genotoxic compounds protein adducts, such as those formed with haemoglobin, are considered effective biomarkers for determining individual exposure doses of reactive chemicals. For other organic chemicals, the excreted urinary metabolites can also give a useful and complementary indication of exposure for acute exposures. These methods have revealed ‘backgrounds’ in people not knowingly exposed to chemicals and the sources and significance of these need to be determined, particularly in the context of their contribution to background health risks.     

Role of biomarkers in monitoring exposures to chemicals: present position, future prospects

Biomarkers are becoming increasingly important in toxicology and human health. Many research groups are carrying out studies to develop biomarkers of exposure to chemicals and apply these for human monitoring. There is considerable interest in the use and application of biomarkers to identify the nature and amounts of chemical exposures in occupational and environmental situations. Major research goals are to develop and validate biomarkers that reflect specific exposures and permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This review presents a commentary and consensus views about the major developments on biomarkers for monitoring human exposure to chemicals. A particular emphasis is on monitoring exposures to carcinogens. Significant developments in the areas of new and existing biomarkers, analytical methodologies, validation studies and field trials together with auditing and quality assessment of data are discussed. New developments in the relatively young field of toxicogenomics possibly leading to the identification of individual susceptibility to both cancer and non-cancer endpoints are also considered. The construction and development of reliable databases that integrate information from genomic and proteomic research programmes should offer a promising future for the application of these technologies in the prediction of risks and prevention of diseases related to chemical exposures. Currently adducts of chemicals with macromolecules are important and useful biomarkers especially for certain individual chemicals where there are incidences of occupational exposure. For monitoring exposure to genotoxic compounds protein adducts, such as those formed with haemoglobin, are considered effective biomarkers for determining individual exposure doses of reactive chemicals. For other organic chemicals, the excreted urinary metabolites can also give a useful and complementary indication of exposure for acute exposures. These methods have revealed 'backgrounds' in people not knowingly exposed to chemicals and the sources and significance of these need to be determined, particularly in the context of their contribution to background health risks.     

Biological monitoring of pesticide exposure: a review of analytical methods

A wide range of studies concerned with analytical methods for biological monitoring of exposure to pesticides is reviewed. All phases of analytical procedures are assessed, including sampling and storage, sample preparation and analysis, and validation of methods. Most of the studies aimed at measuring metabolites or unchanged compounds in urine and/or blood as biological indicators of exposure or dose. Biological indicators of effect, such as cholinesterase, are also evaluated. The principal groups of pesticides are considered: organophosphorus pesticides, carbamate pesticides, organochlorine pesticides, pyrethroid pesticides, herbicides, fungicides and other compounds. Choice of the method for biological monitoring of exposure depends on the study population: a detection limit of 1 microg/l or less is required for the general population; higher values are adequate for occupationally exposed subjects. Interpretation of results is also discussed. Since biological indices of exposure are only available for a few compounds, biological reference values, established for the general population, may be used for comparison with levels of professionally exposed subjects.     

Quality assurance of biological monitoring in occupational and environmental medicine

Biological monitoring of chemical exposure in the workplace has become increasingly important in the assessment of health risk as an integral part of the overall occupational health and safety strategy. In environmental medicine biological monitoring plays also an important role in the assessment of excessive, acute or chronic exposure to chemical agents. To guarantee that the results obtained in biological monitoring are comparable with threshold limit values and results from other laboratories, the analysis must be carried out with tested and reliable analytical methods and accompanied by a quality assurance scheme. Confounding influences and interferences during the pre-analytical phase can be minimised by recommendations from experienced laboratories. For internal quality control commercially available control samples with an assigned concentration are used. External quality control programs for biological monitoring are offered by several institutions. The external quality control program of the German Society of Occupational and Environmental Medicine has been organised since 1982. In the meantime the 27th program has been carried out offering 96 analytes in urine, blood and plasma for 47 substances. This program covers most of the parameters relevant to occupational and environmental medicine. About 350 laboratories take part in these intercomparison programs. At present, ten German and 14 international laboratories are commissioned to determine the assigned values. The data evaluated from the results of the intercomparison programs give a good overview of the current quality of the determination of analytes assessed in occupational and environmental toxicological laboratories. For the analysis of inorganic substances in blood and urine the tolerable variation ranges from 7.5 to 43.5%. For organic substances in urine the tolerable variation ranges from 12 to 48%. The highest variations (36-60%) were found for the analysis of organochlorine compounds in plasma. The tolerable variations for the determination of solvents in blood by head space gas chromatography range from 26 to 57%. If the recommendations for the pre-analytical phase, the selection of reliable analytical methods by the laboratory and the carrying out of adequate quality control are observed, the pre-requisites for reliable findings during biological monitoring are fulfilled     

Recommended Best Practices for Process Monitoring Instrumentation in Pharmaceutical Freeze Drying—2017

Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented, focusing on methods that apply to both laboratory and production scale. With respect to product temperature measurement, sources of uncertainty associated with any type of measurement probe are discussed, as well as important differences between the two most common types of temperature-measuring instruments—thermocouples and resistance temperature detectors (RTD). Two types of pressure transducers are discussed—thermal conductivity-type gauges and capacitance manometers, with the Pirani gauge being the thermal conductivity-type gauge of choice. It is recommended that both types of pressure gauge be used on both the product chamber and the condenser for freeze dryers with an external condenser, and the reasoning for this recommendation is discussed. Developing technology for process monitoring worthy of further investigation is also briefly reviewed, including wireless product temperature monitoring, tunable diode laser absorption spectroscopy at manufacturing scale, heat flux measurement, and mass spectrometry as process monitoring tools.     

Tradescantia stamen-hair system as an excellent botanical tester of mutagenicity: its responses to ionizing radiations and chemical mutagens, and some synergistic effects found.

The stamen-hair system of Tradescantia heterozygous for flower color (blue/pink, the pink color being recessive) is an excellent botanical tester of mutagenicity. It is especially useful for detection of the genetic effects of both ionizing radiations and chemical mutagens at the low levels of exposure to which the human population may actually be exposed. This system exhibits a high accuracy in laboratory experiments, and is also applicable for in situ monitoring in the environment. The use of the Tradescantia stamen-hair system is inexpensive and requires only a short training time. Simplified scoring methods which endorse a high statistical accuracy have newly been developed to score larger samples of pink somatic mutations. In the present paper, the most widely used clones, methods for their cultivation, and use in a variety of experiments with radiations and chemical mutagens are also reviewed.     

底栖硅藻应用于河流生态系统健康评价的研究进展

硅藻是水生态系统中最重要的初级生产者之一, 不仅为生态系统中其他消费者提供碳源, 也因分布广泛、种类多、世代时间短等特点, 通常被认为是水环境及生态系统良好的指示生物。文章介绍了河流生态系统健康及生物完整性的概念, 综述了硅藻尤其是底栖硅藻在水生态系统中的自身特点及作用; 概述了硅藻在生物监测中广泛应用的前提: 对环境因子的响应和国内外对硅藻及硅藻指数在河流生态监测中的研究进展; 介绍了广泛应用的硅藻指数及基于硅藻的生物完整性指数的原理及构建方法; 指出了硅藻及硅藻指数在生物监测及评价中可能所存在的问题, 并提出了今后我国在这个领域后期需开展的工作。     

浒苔遥感监测研究进展

浒苔大规模集聚形成的绿潮灾害是海洋生态系统主要生态环境问题之一,基于卫星遥感影像监测浒苔及其扩展动态已成为一种及时有效的手段。对国内外浒苔遥感监测方面文献进行归纳整理,认为光学遥感数据、多波段比值法是最常用的遥感数据和监测方法。对遥感监测浒苔机理进行了阐述,并对分类方法进行评价认为监督分类法解译精度不高。目前单波段阈值法和多波段比值法应用广泛,但在监测漂浮浒苔和混合象元解译存在不足。辐射传输模型法能有效提高信息解译的精度,但还处于起步阶段。遥感监测浒苔灾害的未来发展需要提高影像空间分辨率,深入研究监测方法,进行多种平台和多源遥感数据相结合,并由定性走向定量,从而建立健全遥感监测预警系统。     

Methods to detect cyanobacteria and their toxins in the environment

Cyanobacteria blooms are since early times a cause for environmental concern because of their negative impact through the release of odors, water discoloration, and more dangerously through the release of toxic compounds (i.e. the cyanotoxins) that can affect both human and animal welfare. Surveillance of the aquatic ecosystems is therefore obligatory, and methods to achieve such require a prompt answer not only regarding the species that are producing the blooms but also the cyanotoxins that are being produced and/or released. Moreover, besides this well-known source of possible intoxication, it has been demonstrated the existence of several other potential routes of exposure, either for humans or other biota such as through food additives and in terrestrial environments (in plants, lichens, biological soil crusts) and the recognition of their harmful impact on less studied ecosystems (e.g. coral reefs). Nowadays, the most frequent approaches to detect toxic cyanobacteria and/or their toxins are the chemical-, biochemical-, and molecular-based methods. Above their particular characteristics and possible applications, they all bring to the environmental monitoring several aspects that are needed to be discussed and scrutinized. The end outcome of this review will be to provide newer insights and recommendations regarding the methods needed to apply in an environmental risk assessment program. Therefore, a current state of the knowledge concerning the three methodological approaches will be presented, while highlighting positive and negative aspects of each of those methods within the purpose of monitoring or studying cyanobacteria and their toxins in the environment.     

寡营养细菌及其在环境科学中的应用

寡营养细菌是生存在寡营养环境中的一类细菌,其多样性与生物量在整个生物圈组成中都具有较大的优势,因而在生物地球化学循环中发挥着重要作用.从20世纪80年代开始,寡营养细菌在自然或人为环境中的寡营养机制、对饥饿的生理反应以及在生态系统中的作用一直是微生物生态学研究的前沿领域之一,其理论价值与应用前景已受到各国微生物生态学家与环境科学家们的广泛重视.本文综述了寡营养细菌的基本概念、营养类型、生理生态特性、可能的寡营养机制、主要研究方法以及在医学细菌检测和环境重金属监测中的应用等,并指出了寡营养细菌在环境科学中的应用前景.     

Models for the analysis of radon-exposed populations

Radon-222 is a radioactive decay product of radium-226 and uranium-238, which are found throughout the crust of the earth. Studies of underground miners clearly show that exposure to radon and its decay products increases the risk of developing lung cancer. Data on standardized mortality ratios from eight cohort studies indicate that the radon-lung cancer relationship is statistically homogeneous, even though cohorts are from different types of mines and from different countries. Regression methods for cohort data based on a Poisson probability model permit a thorough consideration of risk patterns. In this report, we review these methods, wherein the disease rate in each cell of a multi-way table is modeled as a function of the cross-classifying variables. The National Academy of Sciences' Committee on the Biological Effects of Ionizing Radiation uses the Poisson regression approach to develop a model for age-specific lung cancer risk which depends on cumulative exposure, age at risk, and time since exposure. This model is reviewed and its implications discussed. The most important determinant of lung cancer is cigarette smoking. This paper discusses relative risk models for analysis of joint exposure to radon and tobacco products. The review of available studies suggests that the joint relationship of radon and smoking with lung cancer is consistent with a multiplicative model, but a submultiplicative relationship is most likely. An additive model is rejected.     

Mercapturic acids as biomarkers of exposure to electrophilic chemicals:applications to environmental and industrial chemicals

The use of mercapturic acids (N-acetyl-L-cysteine S-conjugates, MAs) in the biological monitoring of human exposure to environmental and industrial chemicals is receiving more and more attention. Mercapturic acids (MAs) are formed from glutathione (GSH) S-conjugates via the MA-pathway. Although this pathway can lead to different end-products, the formation of MAs is the predominant route in most species, including man. Two GSH S-transferases (GSTs) show genetic polymorphisms in humans and this can have major consequences for individual susceptibility to toxic effects and for MA formation. In occupational toxicology, adducts to biomacromolecules are also used as biomarkers. DNA adducts are a measure for the effective dose, while protein adducts are related to the dose at critical site. Both type of adducts are normally determined in blood, while MAs are determined in urine. Most MAs are excreted with relatively short half-lifes, allowing a direct evaluation of the occupational circumstances. For many compounds similar (linear) dose-dependency was found for MA excretion, formation of macromolecular adducts, and for various biomarkers of toxic effects. These relations together with fact that MAs relate to the electrophilic character of compounds, allows for the conclusion that MAs are biomarkers of toxicologically relevant internal doses of chemicals or their metabolites. An overview will be given here of the use of MAs in the assessment of internal human exposure to electrophilic environmental and industrial chemicals. Additionally, the formation of GSH S-conjugates, their catabolism to MAs and several of the frequently used analytical approaches are discussed. When appropriate, the influence of genetic polymorphisms on formation of MAs and on susceptibility to toxicity will be discussed for different chemicals as well.     

A Review of Methods for Non-Invasive Heart Rate Measurement on Wrist

When evaluating general health condition on a patient, heart rate is an essential indicator as it is directly representative of the cardiac system state. Continuous measurement methods of heart rate are required for ambulatory monitoring involved in preliminary diagnostic indicators of cardiac diseases or stroke. The growing number of recent developments in wearable devices is reflective of the increasing demand in wrist-worn activity trackers for fitness and health applications. Indeed, the wrist represents a convenient location in terms of form factor and acceptability for patients. While most commercially-available devices are based on optical methods for heart rate measurement, others methods were also developed, based on various physiological phenomena. This review is focused on heart rate measurement methods located on forearm and more specifically on the wrist. For each method, the physiological mechanism involved is described, and the associated transducers for bio-signal acquisition as well as practical developments and prototypes are presented. Methods are discussed on their advantages, limitations and their suitability for an ambulatory use. More specifically, the superposition of motion artefacts over the signal of interest is one of the largest drawbacks for these methods, when used out of laboratory conditions. As such, artefact reduction techniques proposed in the literature are also presented and discussed.     

Mercapturic acids as biomarkers of exposure to electrophilic chemicals:applications to environmental and industrial chemicals

The use of mercapturic acids (N-acetyl-L-cysteine S-conjugates, MAs) in the biological monitoring of human exposure to environmental and industrial chemicals is receiving more and more attention. Mercapturic acids (MAs) are formed from glutathione (GSH) S-conjugates via the MA-pathway. Although this pathway can lead to different end-products, the formation of MAs is the predominant route in most species, including man. Two GSH S-transferases (GSTs) show genetic polymorphisms in humans and this can have major consequences for individual susceptibility to toxic effects and for MA formation. In occupational toxicology, adducts to biomacromolecules are also used as biomarkers. DNA adducts are a measure for the effective dose, while protein adducts are related to the dose at critical site. Both type of adducts are normally determined in blood, while MAs are determined in urine. Most MAs are excreted with relatively short half-lifes, allowing a direct evaluation of the occupational circumstances. For many compounds similar (linear) dose-dependency was found for MA excretion, formation of macromolecular adducts, and for various biomarkers of toxic effects. These relations together with fact that MAs relate to the electrophilic character of compounds, allows for the conclusion that MAs are biomarkers of toxicologically relevant internal doses of chemicals or their metabolites. An overview will be given here of the use of MAs in the assessment of internal human exposure to electrophilic environmental and industrial chemicals. Additionally, the formation of GSH S-conjugates, their catabolism to MAs and several of the frequently used analytical approaches are discussed. When appropriate, the influence of genetic polymorphisms on formation of MAs and on susceptibility to toxicity will be discussed for different chemicals as well.     

Proteomics of allergens

The present state of proteomics research is generally outlined and the character of allergenic compounds briefly elucidated. The principles of experimental approaches to isolation, purification, identification and characterization of allergens and to monitoring of their biological activity are described, with emphasis on the most modern methods. Selected examples are given for illustration and important results are summarized in tables.     

An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system

In its White Paper, "Strategy for a Future Chemicals Policy," published in 2001, the European Commission (EC) proposed the REACH (Registration, Evaluation and Authorisation of CHemicals) system to deal with both existing and new chemical substances. This system is based on a top-down approach to toxicity testing, in which the degree of toxicity information required is dictated primarily by production volume (tonnage). If testing is to be based on traditional methods, very large numbers of laboratory animals could be needed in response to the REACH system, causing ethical, scientific and logistical problems that would be incompatible with the time-schedule envisaged for testing. The EC has emphasised the need to minimise animal use, but has failed to produce a comprehensive strategy for doing so. The present document provides an overall scheme for predictive toxicity testing, whereby the non-animal methods identified and discussed in a recent and comprehensive ECVAM document, could be used in a tiered approach to provide a rapid and scientifically justified basis for the risk assessment of chemicals for their toxic effects in humans. The scheme starts with a preliminary risk assessment process (involving available information on hazard and exposure), followed by testing, based on physicochemical properties and (Q)SAR approaches. (Q)SAR analyses are used in conjunction with expert system and biokinetic modelling, and information on metabolism and identification of the principal metabolites in humans. The resulting information is then combined with production levels and patterns of use to assess potential human exposure. The nature and extent of any further testing should be based strictly on the need to fill essential information gaps in order to generate adequate risk assessments, and should rely on non-animal methods, as far as possible. The scheme also includes a feedback loop, so that new information is used to improve the predictivity of computational expert systems. Several recommendations are made, the most important of which is that the European Union (EU) should actively promote the improvement and validation of (Q)SAR models and expert systems, and computer-based methods for biokinetic modelling, since these offer the most realistic and most economical solution to the need to test large numbers of chemicals.     

The genus Eurydice on the west coast of India

An ecological survey of the sandy beaches of the west coast of India revealed an important population of eurydicid isopods ( Eurydice peraticis Jones; E. indicis sp. nov.) of which one species is new to science. The systematics of these isopods are described, and their distribution on the Arabian Sea coast and the Indian beaches is discussed. Differences in their horizontal and vertical distribution on the beaches are explained in relation to the prevailing environmental conditions, of which exposure is the most important.     

A cautionary comment on the generation of Berkson error in epidemiological studies

Exposure measurement error can be seen as one of the most important sources of uncertainty in studies in epidemiology. When the aim is to assess the effects of measurement error on statistical inference or to compare the performance of several methods for measurement error correction, it is indispensable to be able to generate different types of measurement error. This paper compares two approaches for the generation of Berkson error, which have recently been applied in radiation epidemiology, in their ability to generate exposure data that satisfy the properties of the Berkson model. In particular, it is shown that the use of one of the methods produces results that are not in accordance with two important properties of Berkson error.     

Estimating occupational exposure to the pyrethroid termiticide bifenthrin by measuring metabolites in urine

The control of subterranean termites in Australia is predominantly through the application of chemical barriers in the soil beneath and surrounding buildings. The chemicals used to repel or kill termites are the organophosphorus insecticide, chlorpyrifos, and the synthetic pyrethroid, bifenthrin. These are applied through surface sprays and subfloor injection by licensed pest control operators. To determine the exposure of these personnel to these pesticides it is most usual to measure airborne concentrations or dermal deposition rates. However, to support information obtained from these methods it is often appropriate to determine the amount of the chemicals absorbed, using biological monitoring techniques including measurement of the chemicals or their metabolites in urine. While there are effective techniques for the monitoring of chlorpyrifos exposure by measuring either the alkyl phosphate or trichloropyridinol metabolites, there have been no published reports of suitable methods to measure bifenthrin metabolites in urine. This paper describes an extraction and HPLC-UV method used to simultaneously measure the urinary excretion of 2-methyl-3-phenylbenzoic acid (MPA), a metabolite of bifenthrin, and 3-phenoxybenzoic acid (PBA), a metabolite of several other common pyrethroid insecticides, with a detection limit for each of 2.5 ng/ml. The paper also describes the pilot application of this method to a study of South Australian pest control operators handling bifenthrin. MPA ranged from 1.8 to 31.9 microg/g creatinine and PBA from 1.3 to 30.0 microg/g in the urine of pest control workers. MPA was detected in urine of control workers without bifenthrin exposure only at low levels (1.0-1.4 microg/g creatinine), but PBA was found in both at higher levels (1.2-61.1 microg/g creatinine).     

The assessment of pesticide hazards to birds: the problem of variable effects

The hazard presented to birds by the use of a particular pesticide is dependent on many factors and may therefore vary in its severity. Even effects which occur very infrequently may sometimes be sufficiently severe to warrant regulatory action. The potential for variability is illustrated by the effects of carbophenothion on geese and of fenitrothion on forest songbirds. Potential for the movements and behaviour of birds to vary their exposure to pesticides is illustrated using data on Tree Sparrows Passer montanus and Brent Geese Branta bernicla . Methods used in the assessment of pesticide effects are reviewed, and their ability to cope with variability is discussed. Further research is required to extend understanding of the mechanisms which cause variability, and to assess the sensitivity of methods for monitoring the effects of pesticides during commercial use.