Risk assessment biomarkers

Extensive research is currently underway to use biological markers (biomarkers) in exposure and risk assessment. Biomarkers include the reaction products of chemicals or their metabolic products with biological macromolecules, especially with DNA. They also involve indicators of effect, such as chromosomal damage, and indicators of individual genetic susceptibility. 

There is a growing need to better characterize the health risk related to occupational and environmental exposure to pesticides. Risk characterization is a basic step in the assessment and management of the health risks related to chemicals (Tordoir and Maroni, 1994). Evaluation of exposure, which may be performed through environmental and biological monitoring, is a fundamental component of risk assessment. Biomarkers are useful tools that may be used in risk assessment to confirm exposure or to quantify it by estimating the internal dose. Besides their use in risk assessment, biomarkers also represent a fundamental tool to improve the effectiveness of medical and epidemiological surveillance. 

If this value is much smaller than unity, the risk is low. If it is unity or above, there is a substantial risk. These calculations only provide rough estimates of risk, and thus the environmental exposure must be considered as well. Such considerations strengthen the case for developing new strategies using biomarkers for risk assessment. Biomarker assays can provide measures of exposure (and sometimes of toxic effects) under actual field conditions. 

Palmer, B.D. and K.W. Selcer. Vitellogenin as a biomarker for xenobiotic estrogens a review. In Environmental Toxicology and Risk Assessment Biomarkers and Risk Assessment, ASTM STP 1306, Vol. 5, edited by D.A. Bengtson and D.S. Henshel, pp. 3-21, 1996. 

Donnelly KC, Phillips TD, Onufrock AM, et al. 1996. Genotoxicity of model and complex mixtures of polycyclic aromatic hydrocarbons. In Bengtson DA, Henshel DS, eds. Environmental toxicology and risk assessment Biomarkers and risk assessment. ASTM STP. Conshohocken, PA ASTM, 138-148. 

Our new appreciation of the role of inflammation in atherosclerosis shows the way for translation of these novel biological insights to clinical practice, for example by aiding the identification of individuals at risk of adverse cardiovascular events [5]. In this context, inflammatory biomarkers such as CRP merit rigorous consideration for inclusion in risk assessment strategies. In addition, these scientific advances provide a framework... 

A biomarker is here defined as a biological response to an environmental chemical at the individual level or below, which demonstrates a departure from normality. Responses at higher levels of biological organization are not, according to this definition, termed biomarkers. Where such biological responses can be readily measnred, they may provide the basis for biomarker assays, which can be nsed to stndy the effects of chemicals in the laboratory or, most importantly, in the field. There is also interest in their employment as tools for the environmental risk assessment of chemicals. 

The development of models incorporating biomarker assays to predict the effects of chemicals upon parameters related to r has obvious attractions from a scientific point of view and is preferable, in theory, to the crude use of ecotoxicity data currently employed in procedures for environmental risk assessment. However, the development of this approach would involve considerable investment in research, and might prove too complex and costly to be widely employed in environmental risk assessment. 

The more difficult thing is to develop models that can, with reasonable confidence, be used to predict ecological effects. A detailed discussion of ecological approaches to risk assessment lies outside the scope of the present text. For further information, readers are referred to Suter (1993) Landis, Moore, and Norton (1998) and Peakall and Fairbrother (1998). One important question, already touched upon in this account, is to what extent biomarker assays can contribute to the risk assessment of environmental chemicals. The possible use of biomarkers for the assessment of chronic pollution and in regulatory toxicology is discussed by Handy, Galloway, and Depledge (2003). 

Another issue is the development and refinement of the testing protocols used in mesocosms. Mesocosms could have a more important role in environmental risk assessment if the data coming from them could be better interpreted. The use of biomarker assays to establish toxic effects and, where necessary, relate them to effects produced by chemicals in the field, might be a way forward. The issues raised in this section will be returned to in Chapter 17, after consideration of the individual examples given in Part 2. 

Thns far, the discussion has dealt primarily with biomarker responses in living organisms. In the next section, consideration will be given to the exploitation of this principle in the development of bioassay systems that can be nsed in environmental monitoring and environmental risk assessment. 

A central theme of this text is the development of biomarker assays to measure the extent of toxic effects caused by chemicals both in the field studies and for the purposes of environmental risk assessment. 

Recently, there has been a growth of interest in the development of in vitro methods for measuring toxic effects of chemicals on the central nervous system. One approach has been to conduct electrophysiological measurements on slices of the hippocampus and other brain tissues (Noraberg 2004, Kohling et al. 2005). An example of this approach is the extracellular recording of evoked potentials from neocortical slices of rodents and humans (Kohling et al. 2005). This method, which employs a three-dimensional microelectrode array, can demonstrate a loss of evoked potential after treatment of brain tissue with the neurotoxin trimethyltin. Apart from the potential of in vitro methods such as this as biomarkers, there is considerable interest in the use of them as alternative methods in the risk assessment of chemicals, a point that will be returned to in Section 16.8. 

There is a continuing interest in the development of biomarker assays for use in environmental risk assessment. As discussed elsewhere (Section 16.6), there are both scientific and ethical reasons for seeking to introduce in vitro assays into protocols for the regulatory testing of chemicals. Animal welfare organizations would like to see the replacement of toxicity tests by more animal-friendly alternatives for all types of risk assessment—whether for environmental risks or for human health. 

Apart from the use of this approach to study the ecotoxicology of neurotoxic pollutants in the field, it also has potential for use during the course of environmental risk assessment. An understanding of the relationship between biomarker responses to neurotoxic compounds and effects at the population level can be gained from both field studies and the use of mesocosms and other model systems. From these it may be possible to define critical thresholds in biomarker responses of indicator species above which population effects begin to appear. In the longer term, this approach... 

At the practical level, an ideal mechanistic biomarker should be simple to use, sensitive, relatively specific, stable, and usable on material that can be obtained by nondestructive sampling (e.g., blood or skin). A tall order, no doubt, and no biomarker yet developed has all of these attributes. However, the judicious use of combinations of biomarkers can overcome the shortcomings of individual assays. The main point to emphasize is that the resources so far invested in the development of biomarker technology for environmental risk assessment has been very small (cf the investment in biomarkers for use in medicine). Knowledge of toxic mechanisms of organic pollutants is already substantial (especially of pesticides), and it grows apace. The scientific basis is already there for technological advance it all comes down to a question of investment. 

Interest has been expressed in the possibility of using biomarker assays as a part of risk assessment for regulatory purposes, and some workers have suggested tiered testing procedures that follow this approach (see, for example, Handy et al. 2003). It is to be hoped that regulatory schemes, such as that of REACH (see European Union 2003), will be sufficiently flexible to incorporate new assays and testing strategies as the science advances. 

Peakall, D.B. and Fairbrother, A. (1998). Biomarkers for monitoring and measuring effects. In P.E.T. Douben (Ed.) Pollution Risk Assessment and Management. Chichester, U.K. John Wiley 351-356. 

Kreps SE, BanzetN, Christiani DC, Polla BS. 1997. Molecular biomarkers of early responses to environmental stressors — implications for risk assessment and pubhc health. Rev Environ Health 12 261-280. 

NOMIRACLE (2004-2009, http //viso.jrc.it/nomiracle/) provided support to the development and improvement of a coherent series of methodologies underpinned by mechanistic understanding, while integrating the risk analysis approaches of environmental and human health. The project delivered understanding of and tools for sound risk assessment, developing a research framework for the description and interpretation of combined stressor effects that leads to the identification of biomarkers and other indicators of cumulative impacts. 

Due to the fact that JP-8 contains hundreds of aliphatic and aromatic hydrocarbons, in addition to various performance additives, this complex mixture poses a serious challenge for risk assessment. Exposure assessment is complicated by the fact that JP-8 may be encountered as a vapor, aerosol, or liquid, and possibly as combustible products, and each physical state may contain different chemical entities. However, progress has been made in the identification of JP-8 components that may serve as reliable and predictable biomarkers of exposure, particularly for dermal exposures [12,35,81,82,83,84],... 

Parrott, J.L. and Tillitt, D.E. 1997,The use of Semipermeable Membrane Devices (SPMDs) to Concentrate Inducers of Fish Hepatic Mixed Function Oxygenase (MFO). In Ecotoxicology Responses, Biomarkers, and Risk Assessment. An OECD Workshop Zelikoff, J.T., Ed. SOS Publications Pair Haven, NJ. pp. 185—196. 

Van der Oost, R. Beyer, J. Vermeulen, N.P.E. 2003, Eish bioaccumulation and biomarkers in environmental risk assessment A review. Environ. Toxicol. Phar. 13 57-149. 

Research Priorities in Environmental Risk Assessment. Held in Breckenridge, Colorado, Aug 16 to 21,1987. Published by SETAC, 1987. Biomarkers Biochemical, Physiological, and Histological Markers of Anthropogenic Stress. Keystone, Colorado, 23 to 28 Jul 1989. Published as a SETAC Special Publication by Lewis Publishers, 1992. 

Apanel of in vivo biomarkers that refiects the different mechanisms of toxicity and that could be used to predict drug response in tissue would be invaluable in hepatotoxicity risk assessment. 

New biomarkers will be useful in hepatotoxicity risk assessment if the data quality and validity can be established. The FDA defines a valid biomarker as one that can be measured in an analytical test system with well-established performance characteristics and has an established scientific framework or body of evidence that elucidates the significance of the test results [160]. Although there is no formerly agreed upon path, biomarker validation should include appropriate end-points for study (i.e., toxicology, histopathology, bioanalytical chemistry, etc.) and dose- and time-dependent measurements. An assessment of species, sex and strain susceptibility is also important to evaluate across species differences. More specific considerations for validation of gene and protein expression technologies are reviewed by Corvi et al. and Rifai et al. [144, 147]. 

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