Exposure and effect monitoring: a critical appraisal of their practical application.

The prerequisite for the use of biomarkers of exposure as indicators of health risk is that the relationship between the biomarker and the health effects and the representation in time of the biomarker level are known. Some exposure biomarkers may be applied for the quantitative assessment of the amount of exposure. In this task, the half-time of the parameter measured is crucial, since it determines what length of time of exposure the result reflects. For reliable assessment of the exposure the species (e.g. metal, oxide or salt) has to be known. For some chemicals the estimation of exposure from biomonitoring is based on several studies with uniform results and is quite reliable, while for others the uncertainty is wide. Exposure biomarkers have been successfully used in the identification of exposed individuals and follow-up of exposure. For example, macromolecule adducts and mutagenicity in urine have been successfully applied to the identification of workers exposed to carcinogens and as indicators of changes of exposure. Biomarkers of renal effects of cadmium, lead effects on haemoglobin synthesis and organophosphate effects on cholinesterase activities have been well validated and are widely used in routine monitoring activities. However, effect markers for lead and cadmium offer little advantage over the analysis of the chemical itself and where accurate metal analysis is readily available, they have a limited use today. For the analysis of chromosomal aberrations, limited data are available suggesting that elevated frequencies may indicate a carcinogenic risk. In several instances, genotoxic effect monitoring has been used to identify groups of people exposed to hazardous chemicals and in the follow-up of improvements in industrial hygiene.     

Human biomonitoring as a pragmatic tool to support health risk management of chemicals--examples under the EU REACH programme

REACH requires health risk management for workers and the general population and introduced the concept of Derived No-Effect Level (DNEL). DNELs must be derived for all substances that are classified as health hazards. As with analogues to other health-risk based guidance values, such as reference doses (RfDs) and tolerable daily intakes (TDIs), risk to health is considered negligible if the actual exposure is less than the DNEL. Exposure assessment is relatively simple for occupational situations but more complex for the general public, in which exposure may occur via multiple pathways, routes, and media. For such complex or partially defined exposure scenarios, human biomonitoring gives a snapshot of internal or absorbed dose of a chemical and is often the most reliable exposure assessment methodology as it integrates exposures from all routes. For human risk management human biomonitoring data can be interpreted using the recently developed concept of Biomonitoring Equivalents (BE). Basically, a BE translates an established reference value into a biomarker concentration using toxicokinetic data. If the results of an exposure assessment using human biomonitoring indicate that the levels measured are below the DNEL-based BE (BE(DNEL)), it would indicate that the combined exposure via all potential exposure routes is unlikely to pose a risk to human health and that health risk management measures might not be needed. Hence, BEs do not challenge existing risk assessments but rather build upon them to help risk management, the ultimate goal of any risk assessment. A challenge in implementing this approach forms the limited availability of toxicokinetic information for many substances. However, methodologies such as generic physiologically-based toxicokinetic models, which allow estimation of biomarker concentrations based on physicochemical properties, are being developed for less data-rich chemicals. Use of BE by regulatory authorities will allow initial screening of population exposure to chemicals to identify those chemicals requiring more detailed risk and exposure assessment, assisting in priority setting and ultimately leading to improved product stewardship and risk management.     

Role of Exhaled Breath Biomarkers in Environmental Health Science

As a discipline of public health, environmental health science is the study of the linkage from environmental pollution sources to eventual adverse health outcome. This progression may be divided into two components, (1) “exposure assessment,” which deals with the source terms, environmental transport, human exposure routes, and internal dose, and (2) “health effects,” which deals with metabolism, cell damage, DNA changes, pathology, and onset of disease. The primary goal of understanding the linkage from source to health outcome is to provide the most effective and efficient environmental intervention methods to reduce health risk to the population. Biomarker measurements address an individual response to a common external environmental stressor. Biomarkers are substances within an individual and are subdivided into chemical markers, exogenous metabolites, endogenous response chemicals, and complex adducts (e.g., proteins, DNA). Standard biomarker measurements are performed in blood, urine, or other biological media such as adipose tissue and lavage fluid. In general, sample collection is invasive, requires medical personnel and a controlled environment, and generates infectious waste. Exploiting exhaled breath as an alternative or supplement to established biomarker measurements is attractive primarily because it allows a simpler collection procedure in the field for numerous individuals. Furthermore, because breath is a gas-phase matrix, volatile biomarkers become more readily accessible to analysis. This article describes successful environmental health applications of exhaled breath and proposes future research directions from the perspective of U.S. Environmental Protection Agency (EPA) human exposure research.     

Role of exhaled breath biomarkers in environmental health science

As a discipline of public health, environmental health science is the study of the linkage from environmental pollution sources to eventual adverse health outcome. This progression may be divided into two components, (1) "exposure assessment," which deals with the source terms, environmental transport, human exposure routes, and internal dose, and (2) "health effects," which deals with metabolism, cell damage, DNA changes, pathology, and onset of disease. The primary goal of understanding the linkage from source to health outcome is to provide the most effective and efficient environmental intervention methods to reduce health risk to the population. Biomarker measurements address an individual response to a common external environmental stressor. Biomarkers are substances within an individual and are subdivided into chemical markers, exogenous metabolites, endogenous response chemicals, and complex adducts (e.g., proteins, DNA). Standard biomarker measurements are performed in blood, urine, or other biological media such as adipose tissue and lavage fluid. In general, sample collection is invasive, requires medical personnel and a controlled environment, and generates infectious waste. Exploiting exhaled breath as an alternative or supplement to established biomarker measurements is attractive primarily because it allows a simpler collection procedure in the field for numerous individuals. Furthermore, because breath is a gas-phase matrix, volatile biomarkers become more readily accessible to analysis. This article describes successful environmental health applications of exhaled breath and proposes future research directions from the perspective of U.S. Environmental Protection Agency (EPA) human exposure research.     

The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity

Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in biological fluids with varying immunoreactivity which can present bioanalytical challenges when first discovered. The potential success of these efforts is greatly enhanced by recent advances in two closely linked technologies, toxicoproteomics and targeted, quantitative mass spectrometry. This review focuses on the examination of the current status of these technologies as they relate to the discovery and development of novel preclinical biomarkers of hepatotoxicity. A critical assessment of the current literature reveals two distinct lines of safety biomarker investigation, (1) peripheral fluid biomarkers of organ toxicity and (2) tissue or cell-based toxicity signatures. Improved peripheral fluid biomarkers should allow the sensitive detection of potential organ toxicity prior to the onset of overt organ pathology. Advancements in tissue or cell-based toxicity biomarkers will provide sensitive in vitro or ex vivo screening systems based on toxicity pathway markers. An examination of the current practices in clinical pathology and the critical evaluation of some recently proposed biomarker candidates in comparison to the desired characteristics of an ideal toxicity biomarker lead this author to conclude that a combination of selected biomarkers will be more informative if not predictive of potential animal organ toxicity than any single biomarker, new or old. For the practical assessment of combinations of conventional and/or novel toxicity biomarkers in rodent and large animal preclinical species, mass spectrometry has emerged as the premier analytical tool compared to specific immunoassays or functional assays. Selected and multiple reaction monitoring mass spectrometry applications make it possible for this same basic technology to be used in the progressive stages of biomarker discovery, development, and more importantly, routine study applications without the use of specific antibody reagents. This technology combined with other “omics” technologies can provide added selectivity and sensitivity in preclinical drug safety testing.     

Biological Effect Markers for Exposure to Carcinogenic Compound and Their Relevance for Risk Assessment

In this review data are summarized on biomarkers that are used for biological effect monitoring of human populations exposed to genotoxic carcinogens. The biomarkers are DNA and protein adducts and cytogenetic effects. Most of these biomarkers are relevant for the process of carcinogenesis. Emphasis is on providing information on the properties of the biomarkers and on their relevance for predicting cancer risk. Overviews are presented of: (1) studies on effects of exposure in target tissues of human origin obtained by surgical biopsies or autopsies, (2) epidemi-ological studies on healthy (cancer-free) individuals, correlating the putative occupational, lifestyle or environmental exposure with increased levels of biomarkers in blood cells, and (3) studies with animal models on the relation between biomarkers and cancer. Finally, on the basis of epidemio-logical data the possibilities were explored to use biomarker data to estimate the risk of death due to cancer. For several biomarkers the increment of the cancer mortality risk was calculated on the basis of a lifetime doubling of the biomarker level.     

Monitoring of human populations for early markers of cadmium toxicity: A review

Exposure of human populations to cadmium (Cd) from air, food and water may produce effects in organs such as the kidneys, liver, lungs, cardiovascular, immune and reproductive systems. Since Cd has been identified as a human carcinogen, biomarkers for early detection of susceptibility to cancer are of an importance to public health. The ability to document Cd exposure and uptake of this element through biological monitoring is a first step towards understanding its health effects. Interpretation and application of biological monitoring data for predicting human health outcomes require correlation with biological measures of organ system responses to the documented exposure. Essential to this understanding is the detection and linkage of early biological responses toxic effects in target cell populations. Fortunately, advances in cell biology have resulted in the development of pre-clinical biological markers (biomarkers) that demonstrate measurable and characteristic molecular changes in organ systems following chemical exposures that occur prior to the onset of overt clinical disease or development of cancer. Technical advances have rendered a number of these biomarkers practical for monitoring Cd-exposed human populations. Biomarkers will be increasingly important in relation to monitoring effects from the exposure to new Cd-based high technology materials. For example, cadmium-selenium (CdSe), nano-materials made from combinations of these elements have greatly altered cellular uptake characteristics due to particle size. These differences may greatly alter effects at the target cell level and hence risks for organ toxicities from such exposures. The value of validated biomarkers for early detection of systemic Cd-induced effects in humans cannot be underestimated due to the rapid expansion of nano-material technologies. This review will attempt to briefly summarize the applications, to date, of biomarker endpoints for assessing target organ system effects in humans and experimental systems from Cd exposure. Further, it will attempt to provide a prospective look at the possible future of biomarkers. The emphasis will be on the detection of early toxic effects from exposure to Cd in new products such as nano-materials and identification of populations at special risk for Cd toxicity.     

Molecular approaches to the identification of biomarkers of exposure and effect--report of an expert meeting organized by COST Action B15. November 28, 2003

In the past, the term biomarker has been used with several meanings when used in human and environmental toxicology as compared to pharmaceutical development. However, with the advent of molecular approaches and their application in the field of drug development and toxicology, the concept of biomarkers has to be newly defined. In the meeting, the experts found consent in defining the term and described the application of biomarkers in toxicology, drug development and clinical diagnostics. Molecular approaches to biomarker identification and selection lead to a large amount of data. Hence, the statistical analysis is challenging and special statistical problems have to be solved in biomarker characterization, of particular interest are attempts aiming at class discovery and prediction. Reliability and biological relevance are to be demonstrated for biomarkers of exposure and effect which is also true for biomarkers of susceptibility. It is envisaged that the application of biomarkers will expand from current use in pre-clinical toxicology to the risk characterization and risk assessment of chemicals and from early clinical phases of drug development to later phases and even into daily clinical use in diagnostics and disease classification.     

Reconstructing Human Exposures Using Biomarkers and other “Clues”

Biomonitoring is the process by which biomarkers are measured in human tissues and specimens to evaluate exposures. Given the growing number of population-based biomonitoring surveys, there is now an escalated interest in using biomarker data to reconstruct exposures for supporting risk assessment and risk management. While detection of biomarkers is de facto evidence of exposure and absorption, biomarker data cannot be used to reconstruct exposure unless other information is available to establish the external exposure–biomarker concentration relationship. In this review, the process of using biomarker data and other information to reconstruct human exposures is examined. Information that is essential to the exposure reconstruction process includes (1) the type of biomarker based on its origin (e.g., endogenous vs. exogenous), (2) the purpose/design of the biomonitoring study (e.g., occupational monitoring), (3) exposure information (including product/chemical use scenarios and reasons for expected contact, the physicochemical properties of the chemical and nature of the residues, and likely exposure scenarios), and (4) an understanding of the biological system and mechanisms of clearance. This review also presents the use of exposure modeling, pharmacokinetic modeling, and molecular modeling to assist in integrating these various types of information.     

Primer for evaluating ecological risk at petroleum release sites

Increasingly, risk-based approaches are being used to guide decision making at sites such as service stations and petroleum product terminals, where petroleum products have been inadvertently released to the soil. For example, the API Decision Support System software, DSS, evaluates site human health risk along six different routes of exposure. The American Society for Testing and Materials' Risk-Based Corrective Action (RBCA) standard, ASTM 1739, establishes a tiered framework for evaluating petroleum release sites on the basis of human health risk. Though much of the risk assessment focus has been on human health risk, regulatory agencies recognize that protection of human health may not fully protect the environment; and EPA has developed guidance on identifying ecological resources to be protected through risk-based decision making. Not every service station or petroleum product terminal site warrants a detailed ecological risk assessment. In some cases, a simple preliminary assessment will provide sufficient information for decision making. Accordingly, the American Petroleum Institute (API) is developing a primer for site managers, to assist them in conducting this preliminary assessment, and in deciding whether more detailed ecological risk assessments are warranted. The primer assists the site manager in identifying relevant ecological receptors and habitats, in identifying chemicals and exposure pathways of concern, in developing a conceptual model of the site to guide subsequent actions, and in identifying conditions that may warrant immediate response.     

On the incorporation of chemical-specific information in risk assessment

This paper describes the evolution of chemical risk assessment from its early dependence on generic default approaches to the current situation in which mechanistic and biokinetic data are routinely incorporated to support a more chemical-specific approach. Two methodologies that have played an important role in this evolution are described: mode-of-action evaluation and physiologically based biokinetic (PBBK) modelling. When used together, these techniques greatly increase the opportunity for the incorporation of biokinetic and mechanistic data in risk assessment. The resulting risk assessment approaches are more appropriately tailored to the specific chemical and are more likely to provide an accurate assessment of the potential hazards associated with human exposures. The appropriate application of PBBK models in risk assessment demands well-formulated statements about the chemical mode of action. It is this requirement for an explicit, mechanistic hypothesis that gives biologically motivated models their power, but at the same time serves as the greatest impediment to the acceptance of a chemical-specific risk assessment approach by regulators. The chief impediment to the regulatory acceptance and application of PBBK models in risk assessment is concern about uncertainties associated with their use. To some extent such concerns can be addressed by the development of generally accepted approaches for model evaluation and quantitative uncertainty analysis. In order to assure the protection of public health while limiting the economic and social consequences of over-regulation, greater dialogue between researchers and regulators is crucially needed to foster an increased use of emerging scientific information and innovative methods in chemical risk assessments.     

Risk assessment of carcinogens in food

Approaches for the risk assessment of carcinogens in food have evolved as scientific knowledge has advanced. Early methods allowed little more than hazard identification and an indication of carcinogenic potency. Evaluation of the modes of action of carcinogens and their broad division into genotoxic and epigenetic (non-genotoxic, non-DNA reactive) carcinogens have played an increasing role in determining the approach followed and provide possibilities for more detailed risk characterisation, including provision of quantitative estimates of risk. Reliance on experimental animal data for the majority of risk assessments and the fact that human exposures to dietary carcinogens are often orders of magnitude below doses used in experimental studies has provided a fertile ground for discussion and diverging views on the most appropriate way to offer risk assessment advice. Approaches used by national and international bodies differ, with some offering numerical estimates of potential risks to human health, while others express considerable reservations about the validity of quantitative approaches requiring extrapolation of dose-response data below the observed range and instead offer qualitative advice. Recognising that qualitative advice alone does not provide risk managers with information on which to prioritise the need for risk management actions, a “margin of exposure” approach for substances that are both genotoxic and carcinogenic has been developed, which is now being used by the World Health Organization and the European Food Safety Authority. This review describes the evolution of risk assessment advice on carcinogens and discusses examples of ways in which carcinogens in food have been assessed in Europe.     

Systematic review of biomonitoring studies to determine the association between exposure to organophosphorus and pyrethroid insecticides and human health outcomes

For the appropriate protection of human health it is necessary to accurately estimate the health effects of human exposure to toxic compounds. In the present review, epidemiological studies on the health effects of human exposure to organophosphorus (OP) and pyrethroid (PYR) insecticides have been critically assessed. This review is focused on studies where the exposure assessment was based on quantification of specific biomarkers in urine or plasma. The 49 studies reviewed used different epidemiological approaches and analytical methods as well as different exposure assessment methodologies. With regard to OP pesticides, the studies reviewed suggested negative effects of prenatal exposure to these pesticides on neurodevelopment and male reproduction. Neurologic effects on adults, DNA damage and adverse birth outcomes were also associated with exposure to OP pesticides. With regard to exposure to PYR pesticides, there are currently few studies investigating the adverse health outcomes due to these pesticides. The effects studied in relation to PYR exposure were mainly male reproductive effects (sperm quality, sperm DNA damage and reproductive hormone disorders). Studies' findings provided evidence to support the hypothesis that PYR exposure is adversely associated with effects on the male reproductive system. The validity of these epidemiological studies is strongly enhanced by exposure assessment based on biomarker quantification. However, for valid and reliable results and conclusions, attention should also be focused on the validity of the analytical methods used, study designs and the measured toxicants characteristics.     

Reconstructing human exposures using biomarkers and other "clues"

Biomonitoring is the process by which biomarkers are measured in human tissues and specimens to evaluate exposures. Given the growing number of population-based biomonitoring surveys, there is now an escalated interest in using biomarker data to reconstruct exposures for supporting risk assessment and risk management. While detection of biomarkers is de facto evidence of exposure and absorption, biomarker data cannot be used to reconstruct exposure unless other information is available to establish the external exposure-biomarker concentration relationship. In this review, the process of using biomarker data and other information to reconstruct human exposures is examined. Information that is essential to the exposure reconstruction process includes (1) the type of biomarker based on its origin (e.g., endogenous vs. exogenous), (2) the purpose/design of the biomonitoring study (e.g., occupational monitoring), (3) exposure information (including product/chemical use scenarios and reasons for expected contact, the physicochemical properties of the chemical and nature of the residues, and likely exposure scenarios), and (4) an understanding of the biological system and mechanisms of clearance. This review also presents the use of exposure modeling, pharmacokinetic modeling, and molecular modeling to assist in integrating these various types of information.     

Primer for Evaluating Ecological risk at Petroleum Release Sites

ABSTRACT

Increasingly, risk-based approaches are being used to guide decision making at sites such as service stations and petroleum product terminals, where petroleum products have been inadvertently released to the soil. For example, the API Decision Support System software, DSS, evaluates site human health risk along six different routes of exposure. The American Society for Testing and Materials' Risk-Based Corrective Action (RBCA) standard, ASTM 1739, establishes a tiered framework for evaluating petroleum release sites on the basis of human health risk. Though much of the risk assessment focus has been on human health risk, regulatory agencies recognize that protection of human health may not fully protect the environment; and EPA has developed guidance on identifying ecological resources to be protected through risk-based decision making.

Not every service station or petroleum product terminal site warrants a detailed ecological risk assessment. In some cases, a simple preliminary assessment will provide sufficient information for decision making. Accordingly, the American Petroleum Institute (API) is developing a primer for site managers, to assist them in conducting this preliminary assessment, and in deciding whether more detailed ecological risk assessments are warranted. The primer assists the site manager in identifying relevant ecological receptors and habitats, in identifying chemicals and exposure pathways of concern, in developing a conceptual model of the site to guide subsequent actions, and in identifying conditions that may warrant immediate response.     

Linking economics and risk assessment

Benefit-cost analysis relies heavily upon risk assessment. The extent to which benefits can be quantitatively included in an economic analysis is frequently determined by risk assessment methods. Therefore, interdisciplinary collaboration between economists and experts in risk assessment-related disciplines is critical to further development of quantitative human health benefits analysis. To further lay the groundwork for such collaborations, this article reviews the economic foundations of benefit-cost analysis, identifies implications of incorporating this approach into risk assessment, and suggests future cooperation between economists and risk assessors.     

Use of epidemiologic data in Integrated Risk Information System (IRIS) assessments

In human health risk assessment, information from epidemiologic studies is typically utilized in the hazard identification step of the risk assessment paradigm. However, in the assessment of many chemicals by the Integrated Risk Information System (IRIS), epidemiologic data, both observational and experimental, have also been used in the derivation of toxicological risk estimates (i.e., reference doses [RfD], reference concentrations [RfC], oral cancer slope factors [CSF] and inhalation unit risks [IUR]). Of the 545 health assessments posted on the IRIS database as of June 2007, 44 assessments derived non-cancer or cancer risk estimates based on human data. RfD and RfC calculations were based on a spectrum of endpoints from changes in enzyme activity to specific neurological or dermal effects. There are 12 assessments with IURs based on human data, two assessments that extrapolated human inhalation data to derive CSFs and one that used human data to directly derive a CSF. Lung or respiratory cancer is the most common endpoint for cancer assessments based on human data. To date, only one chemical, benzene, has utilized human data for derivation of all three quantitative risk estimates (i.e., RfC, RfD, and dose-response modeling for cancer assessment). Through examples from the IRIS database, this paper will demonstrate how epidemiologic data have been used in IRIS assessments for both adding to the body of evidence in the hazard identification process and in the quantification of risk estimates in the dose-response component of the risk assessment paradigm.     

The role of existing and novel cardiac biomarkers for cardioprotection

Cardioprotection is an all-encompassing term for physico-biochemical or therapeutic interventions which slow or ameliorate the progression of cardiomyocyte necrosis. There are a number of established and novel biomarkers to assess coronary artery disease at initiation, ischemia, necrosis and myocardial dysfunction. Established biomarkers such as creatine kinase-MB, cardiac troponins and natriuretic peptides have been utilized for the assessment of cardioprotection, especially during surgery. Novel markers are currently being investigated for detection and risk assessment in patients with acute coronary syndromes. Ischemia-modified albumin is used for the early detection of cardiac ischemia and could be a potential biomarker for assessing the early cardioprotective effects of damage-limiting interventional measures.