DNA modification in carcinogen risk assessment in relation to diet: recent advances and some perspectives from a MAFF workshop

Food is one of the ultimate complex mixtures to which man is exposed and which cannot easily be dispensed with. Apart from certain well studied microcomponents for example, food pyrolysates, Sugimura 1990 human exposure to genotoxic agents arising from macrocomponents has been relatively little studied from the standpoint of DNA damage. The results of epidemiological studies into the relationship between diet and cancer have left many researchers with the impression that it is an intrinsically intractable problem which is perhaps best left well alone. However, given the popular conception that the normal human diet is safe and that such risks as there may be are due to contamination by pesticide and other chemical residues, there is clearly a need to evaluate the possible avenues open to investigators and which are likely to yield meaningful results which would enable scientifically based advice to be given to the public as to the best dietary habits. This overview of the current state of methodology for measurement of DNA damage in relation to diet as well as a summary of current MAFF supported work and future prospects in this area arose out of a workshop entitled DNA modification in carcinogen risk assessment held in London on November 18, 1996 . The object of this report is to summarize the results presented at the workshop and also to indicate the significance of the MAFF funded programme within the broader context of recently published studies from the international scientific community. Hence, a comprehensive review of all aspects of diet related DNA damage is beyond the scope of this article. The workshop was organized as part of the MAFF Risk Assessment Research Programme and contributes to an interdepartmental initiative, the Government Research Councils Initiative on Risk Assessment and Toxicology RATSC which aims to bring together regulators and toxicologists to discuss their respective perspectives on current problems in the risk assessment of chemicals. Further aims of RATSC are to identify subjects for future detailed workshops on specific issues and to identify priorities for research into toxic chemical risk assessment. The membership of RATSC is drawn from a wide range of Government Departments and Research Councils and is chaired by Dr David Shannon MAFF Chief Scientist .     

EC/US workshop report: assessment of genetic risks associated with exposure to ethylene oxide, acrylamide, 1,3-butadiene and cyclophosphamide

The EC/US Workshop on Risk Assessment: ‘Human Genetic Risks from Exposure to Chemicals, Focusing on the Feasibility of a Parallelogram Approach’ had as its main objective the identification of the methodology, data requirements and mechanistic research to understand the human health impact of germ cell mutagens. Specifically, it represented an evaluation of current knowledge and the identification of future research needs for a more precise assessment of human genetic risks from exposure to mutagenic chemicals. Four chemicals were selected for review at the Workshop and in this Special Issue: ethylene oxide, 1,3-butadiene, acrylamide, and cyclophosphamide. The first three are important industrial chemicals with substantial use worldwide and, therefore, considerable potential for human exposure. The fourth, cyclophosphamide, is a commonly used cancer chemotherapeutic agent. This Special Issue contains the major scientific reports from the workshop. These include four Introductory Papers (on the parallelogram concept, alternative genetic risk assessment approaches, regulatory data needs, and the research background for risk assessment of ethylene oxide), four Working Group Reports on the specific compounds mentioned above and, finally, three Crosscutting Papers pertinent to the issue of germ-line mutagenesis and genetic risk estimation.     

Framework for Human Health Risk Assessment

The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the USEPA. The U.S. Government has the right to retain a nonexclusive royalty-free license in and to any copyright covering this article. The U.S. Environmental Protection Agency has recognized the need to develop a framework for human health risk assessment that puts a perspective on the approaches in practice throughout the Agency. In response, the USEPA's Risk Assessment Forum has begun the process of developing a framework for human health risk assessment. This paper provides some additional background to the previous review of the framework efforts and notes the Agency's extramural efforts to begin the process of integrating and harmonizing risk assessment approaches for all human health endpoints.     

The use of biomarkers for improved retrospective exposure assessment in epidemiological studies: summary of an ECETOC workshop

During a scientific workshop the use of biological monitoring in characterization of retrospective exposure assessment was discussed. The workshop addressed currently available methodology and also novel approaches such as in different fields of ‘omics’. For use in epidemiology requiring retrospective exposure assessment, biomarker levels should not vary too much over time. If variability in exposure over time is large and differences in exposure between individuals are relatively small, this may lead to underestimation of the exposure–response relationship. This means that, for a sound assessment of health risk, biomarkers that reflect cumulative exposure over a long period of time are preferred over biomarkers with short half-lives. Most of the existing biomarkers such as metabolites in body fluids usually have rather short half-lives, typically less than 1–2 days. Some adducts to DNA show somewhat longer half-lives. The current limit to persistence of biomarkers reflecting cumulative exposure over time is from adducts to haemoglobin with a half-life of 4 months. Some specific organic substances may be more persistent due to storage in adipose tissue or metals in kidneys, nails and hair. The metabonomics, proteomics and present gene expression profiling approaches do not provide a perspective to the availability of more persistent biomarkers and most approaches discussed to date show that it is difficult to interpret study outcomes in terms of exposure to a specific xenobiotic factor. Research efforts should focus on improvement and validation of currently available approaches in the field of addition products to DNA and proteins. Promising new developments may be phosphotriester DNA adducts and adducts to more long-lived proteins such as histones.     

Epigenetic processes and cancer risk assessment

The U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment encourages the use of mechanistic data in the assessment of human cancer risk at low (environmental) exposure levels. The key events that define a particular mode of action for tumor formation have been concentrated to date more on mutational responses that are broadly the result of induced DNA damage and enhanced cell proliferation. While it is clear that these processes are important in terms of tumor induction, other modes that fall under the umbrella of epigenetic responses are increasingly being considered to play an important role in susceptibility to tumor induction by environmental chemicals and as significant modifiers of tumor responses. Alterations in gene expression, DNA repair, cell cycle control, genome stability and genome reprogramming could be the result of modification of DNA methylation and chromatin remodeling patterns as a consequence of exposure to environmental chemicals. These concepts are described and discussed.     

Framework for Human Health Risk Assessment

The U.S. Environmental Protection Agency has recognized the need to develop a framework for human health risk assessment that puts a perspective on the approaches in practice throughout the Agency. In response, the Agency's Risk Assessment Forum has begun the long-term process of developing a framework for human health risk assessment. The framework will be a communication piece that will lay out the scientific basis, principles, and policy choices underlying past and current risk assessment approaches and will provide recommendations for integrating/harmonizing risk assessment methodologies for all human health endpoints.     

Workshop aims,outline of the program

This workshop on the Technology Assessment of PACS has been organized as a rounding off of the Technology Assessment Activities which were initiated within the Dutch PACS Project (1986–1989). It is made possible by a funding from the Dutch Ministry of Health Care (WVC). We hope it will be not only a rounding off, but will contribute to more intensive cooperations in this area. In the scope of the Dutch PACS project, the software package CAPACITY for cost analyses of PACS has been developed, to stimulate the dialogue and exchange of data. During the workshop, the data which were collected with CAPACITY are used as a framework for discussions. This paper presents the outline of the workshop, its background, its aims and the program.     

The Apache Longbow–Hellfire Missile Test at Yuma Proving Ground: Ecological Risk Assessment for Missile Firing

A multiple stressor risk assessment was conducted at Yuma Proving Ground, Arizona, as a demonstration of the Military Ecological Risk Assessment Framework. The focus was a testing program at Cibola Range, which involved an Apache Longbow helicopter firing Hellfire missiles at moving targets, that is, M60-A1 tanks. This article describes the ecological risk assessment for the missile launch and detonation. The primary stressor associated with this activity was sound. Other minor stressors included the detonation impact, shrapnel, and fire. Exposure to desert mule deer (Odocoileus hemionus crooki) was quantified using the Army sound contour program BNOISE2, as well as distances from the explosion to deer. Few effects data were available from related studies. Exposure-response models for the characterization of effects consisted of human “disturbance” and hearing damage thresholds in units of C-weighted decibels (sound exposure level) and a distance-based No-Observed-Adverse-Effects Level for moose and cannonfire. The risk characterization used a weight-of-evidence approach and concluded that risk to mule deer behavior from the missile firing was likely for a negligible number of deer, but that no risk to mule deer abundance and reproduction is expected.     

生态风险评价研究进展

20多年来,生态风险评价研究经历了从环境风险到生态风险到区域生态风险评价的发展历程,风险源由单一风险源扩展到多风险源,风险受体由单一受体发展到多受体,评价范围由局地扩展到区域景观水平.区域生态风险评价就是大尺度上研究复杂环境背景下包含多风险源、多风险受体的综合风险研究.目前,区域生态风险评价的理论框架已经搭建起来,统计方法多采用相对评价法.区域生态风险评价未来的发展方向为继续加强实验和野外调查,进一步减小不确定性,逐步解决尺度推移问题.区域生态风险评价必须与经济、社会、文化相结合,才能充分发挥它在管理决策中的作用.     

Response to challenging dose of X-rays as a predictive assay for molecular epidemiology

Human biomonitoring, as a tool to identify health risk from environmental exposures, has gained increasing interest especially in the areas of cancer risk assessment and response to therapy. Chromosome aberrations resulting from direct DNA breakage or from inhibition of DNA repair or synthesis, as measured in peripheral blood lymphocytes, have been used successfully in the assessment of environmental health. Susceptibility to the induction of genotoxicity has been evaluated by the use of an in vitro challenge dose of UV or X-rays. In this report, DNA damage was analyzed with the use of single cell gel electrophoresis (SCGE) assay in healthy donors and cancer patients. Studies have shown a good correlation between DNA damage induced in vivo or in vitro and cytogenetic measures. Results from studies on susceptibilities and repair competence in 475 controls, exposed workers and cancer patients are discussed. The possible effects of exposures and influence of the diet and other confounding factors are shown. The prospective use of a challenging dose of radiation combined with the SCGE assay as a predictive assay is suggested and the limitations are discussed.     

Ecological Risk Assessment Guidance and Procedural Documents: An Annotated Compilation and Evaluation of Reference Materials

The scientific approach toward ecological risk assessment (ERA) has advanced greatly during the 1990s. This growth has been accompanied by the development of ERA guidance by USEPA Headquarters, individual USEPA Regions, state environmental agencies, as well as international agencies. This compilation of ERA guidance and procedural documents identifies many of the existing ERA reference materials from the regulatory and/or governmental agency arena. In addition, this compilation provides annotations pertaining to the focus of each reviewed document, and compares/contrasts the approaches presented in the documents. As such, the evaluation provides insight into some of the qualities and levels of detail provided by each document. Examples of documents which are highlighted include recently published USEPA's “Guidelines for Ecological Risk Assessment;” USEPA's “Ecological Risk Assessment Guidance for Superfund;” the U.S. Army's “Procedural Guidelines for Ecological Risk Assessments;” and Environment Canada's “Ecological Risk Assessments Under the Canadian Environmental Protection Act.”     

Improving Risk Assessment: Toxicological Research Needs

A workshop convened to define research needs in toxicology identified several deficiencies in data and methods currently applied in risk assessment. The workshop panel noted that improving the link between chemical exposure and toxicological response requires a better understanding of the biological basis for inter-and intra-human variability and susceptibility. This understanding will not be complete unless all life stages are taken into consideration. Because animal studies serve as a foundation for toxicological assessment, proper accounting for cross-species extrapolation is essential. To achieve this, adjustments for dose-rate effects must be improved, which will aid in extrapolating toxicological responses to low doses and from short-term exposures. Success depends on greater use of validated biologically based dose-response models that include pharmacokinetic and pharmacodynamic data. Research in these areas will help define uncertainty factors and reduce reliance on underlying default assumptions. Throughout the workshop the panel recognized that biomedical science and toxicology in particular is on the verge of a revolution because of advances in genomics and proteomics. Data from these high-output technologies are anticipated to greatly improve risk assessment by enabling scientists to better define and model the elements of the relationship between exposure to biological hazards and health risks in populations with differing susceptibilities.     

Considerations in the U.S. Environmental Protection Agency's testing approach for mutagenicity.

OPP: This paper provides the rationale and support for the decisions the OPP will make in requiring and reviewing mutagenicity information. The regulatory requirement for mutagenicity testing to support a pesticide registration is found in the 40 CFR Part 158. The guidance as to the specific mutagenicity testing to be performed is found in the OPP's Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Animals (referred to as the Subdivision F guideline). A revised Subdivision F guideline has been presented that becomes the current guidance for submitters of mutagenicity data to the OPP. The decision to revise the guideline was the result of close examination of the version published in 1982 and the desire to update the guidance based on developments since then and current state-of-the-science. After undergoing Agency and public scrutiny, the revised guideline is to be published in 1991. The revised guideline consists of an initial battery of tests (the Salmonella assay, an in vitro mammalian gene mutation assay and an in vivo cytogenetics assay which may be either a bone marrow assay for chromosomal aberrations or for micronuclei formation) that should provide an adequate initial assessment of the potential mutagenicity of a chemical. Follow-up testing to clarify results from the initial testing may be necessary. After this information as well as all other relevant information is obtained, a weight-of-evidence decision will be made about the possible mutagenicity concern a chemical may present. Testing to pursue qualitative and/or quantitative evidence for assessing heritable risk in relation to human beings will then be considered if a mutagenicity concern exists. This testing may range from tests for evidence of gonadal exposure to dominant lethal testing to quantitative tests such as the specific locus and heritable translocation assays. The mutagenicity assessment will be performed in accordance with the Agency's Mutagenicity Risk Assessment Guidelines. The mutagenicity data would also be used in the weight-of-evidence consideration for the potential carcinogenicity of a chemical in accordance with the Agency's Carcinogen Risk Assessment Guidelines. In instances where there are triggers for carcinogenicity testing, mutagenicity data may be used as one of the triggers after a consideration of available information. It is felt that the revised Subdivision F guideline will provide appropriate, and more specific, guidance concerning the OPP approach to mutagenicity testing for the registration of a pesticide. It also provides a clearer understanding of how the OPP will proceed with its evaluation and decision making concerning the potential heritable effects of a test chemical.(ABSTRACT TRUNCATED AT 400 WORDS)     

Use of genomic data in risk assessment

A report on the Contemporary Concepts in Toxicology workshop 'Use of Genomic Data in Risk Assessment: State of the Art 2001' held by the Society of Toxicology, Washington DC, USA, 7-8 November 2001.     

Dietary modulation of DNA damage in human

Manipulation of human diet can modulate urinary biomarkers of oxidative DNA base damage (UBODBD), reflecting changes in levels of DNA damage. When dietary composition is maintained but caloric intake is decreased (caloric restriction), UBODBD excretion is suppressed. At isocaloric dietary intake the level of damage depends on diet composition. For diets consisting of foods containing carbohydrates, proteins, and fats but lacking fruits and vegetables, the level of damage is higher than for diets including fruits and vegetables, which are rich in natural antioxidants. Assay of urinary biomarkers is suggested as a potential test for quantitative assessment of the carcinogenic or anticarcinogenic properties of foods, food components, and diets and for individual responses to nutritional regimens.     

Improving Risk Assessment: Priorities for Epidemiologic Research

The Epidemiology Work Group at the Workshop on Future Research for Improving Risk Assessment Methods, Of Mice, Men, and Models, held August 16 to 18, 2000, at Snowmass Village, Aspen, Colorado, concluded that in order to improve the utility of epidemiologic studies for risk assessment, methodologic research is needed in the following areas: (1) aspects of epidemiologic study designs that affect doseresponse estimation; (2) alternative methods for estimating dose in human studies; and (3) refined methods for dose-response modeling for epidemiologic data. Needed research in aspects of epidemiologic study design includes recognition and control of study biases, identification of susceptible subpopulations, choice of exposure metrics, and choice of epidemiologic risk parameters. Much of this research can be done with existing data. Research needed to improve determinants of dose in human studies includes additional individual-level data (e.g., diet, co-morbidity), development of more extensive human data for physiologically based pharmacokinetic (PBPK) dose modeling, tissue registries to increase the availability of tissue for studies of exposure/dose and susceptibility biomarkers, and biomarker data to assess exposures in humans and animals. Research needed on dose-response modeling of human studies includes more widespread application of flexible statistical methods (e.g., general additive models), development of methods to compensate for epidemiologic bias in dose-response models, improved biological models using human data, and evaluation of the benchmark dose using human data. There was consensus among the Work Group that, whereas most prior risk assessments have focused on cancer, there is a growing need for applications to other health outcomes. Developmental and reproductive effects, injuries, respiratory disease, and cardiovascular disease were identified as especially high priorities for research. It was also a consensus view that epidemiologists, industrial hygienists, and other scientists focusing on human data need to play a stronger role throughout the risk assessment process. Finally, the group agreed that there was a need to improve risk communication, particularly on uncertainty inherent in risk assessments that use epidemiologic data.     

Similarities,Differences and Synergisms Between HERA and LCA—An Analysis at Three Levels

Linkages between Human and Environmental Risk Assessment (HERA) and Life-Cycle Assessment (LCA) can be analyzed at three levels: the basic equations to describe environmental behavior and dose-response relationships of chemicals; the overall model structure of these tools; and the applications of the tools. At level 1 few differences exist: both tools use essentially the same fate and effect models, including their coefficients and data. At level 2 distinctive differences emerge: regional or life-cycle perspective, emission pulses or fluxes, scope of chemicals and types of impacts, use of characterization factors, spatial and temporal detail, aggregation of effects, and the functional unit as basis of the assessment. Although the two tools typically differ in all these aspects, only the functional unit issue renders the tools fundamentally different, expressing itself also in some main characteristics of the modeling structure. This impedes full integration, which is underpinned in mathematical terms. At level 3 the aims of the tools are complementary: quantified risk estimates of chemicals for HERA versus quantified product assessment for LCA. Here, beneficial synergism is possible between the two tools, as illustrated by some cases. These also illustrate that where full integration is suggested, in practice this is not achieved, thus in fact supporting the conclusions.     

Harmonization: Developing Consistent Guidelines for Applying Mode of Action and Dosimetry Information to Cancer and Noncancer Risk Assessment

The 1983 book, Risk Assessment in the Federal Government: Managing the Process, recommended developing consistent inference guidelines for cancer risk assessment. Over the last 15 years, extensive guidance have been provided for hazard assessment for cancer and other endpoints. However, as noted in several recent reports, much less progress has occurred in developing consistent guidelines for quantitative dose response assessment methodologies. This paper proposes an approach for dose response assessment guided by consideration of mode of action (pharmacodynamics) and tissue dosimetry (pharmacokinetics). As articulated here, this systematic process involves eight steps in which available information is integrated, leading first to quantitative analyses of dose response behaviors in the test species followed by quantitative analyses of relevant human exposures. The process should be equally appropriate for both cancer and noncancer endpoints. The eight steps describe the necessary procedures for incorporating mechanistic data and provide multiple options based upon the mode of action by which the chemical causes the toxicity. Given the range of issues involved in developing such a procedure, we have simply sketched the process, focusing on major approaches for using toxicological data and on major options; many details remain to be filled in. However, consistent with the revised carcinogen risk assessment guidance (USEPA, 1996c), we propose a process that would ultimately utilize biologically based or chemical specific pharmacokinetic and pharmacodynamic models as the backbone of these analyses. In the nearer term, these approaches will be combined with analysis of data using more empirical models including options intended for use in the absence of detailed information. A major emphasis in developing any harmonized process is distinguishing policy decisions from those decisions that are affected by the quality and quantity of toxicological data. Identification of data limitations also identifies areas where further study should reduce uncertainty in the final risk evaluations. A flexible dose response assessment procedure is needed to insure that sound toxicological study results are appropriately used to influence risk management decision-making and to encourage the conduct of toxicological studies oriented toward application for dose response assessments.     

The Apache Longbow–Hellfire Missile Test at Yuma Proving Ground: Ecological Risk Assessment for Helicopter Overflight

A multi-stressor risk assessment was conducted at Yuma Proving Ground, Arizona, as a demonstration of the Military Ecological Risk Assessment Framework. The focus of the assessment was a testing program at Cibola Range, which involved an Apache Longbow helicopter firing Hellfire missiles at moving targets, that is, M60-A1 tanks. This article focuses on the wildlife risk assessment for the helicopter overflight. The primary stressors were sound and the view of the aircraft. Exposure to desert mule deer (Odocoileus hemionus crooki) was quantified using Air Force sound contour programs NOISEMAP and MR_NMAP, which gave very different results. Slant distance from helicopters to deer was also used as a measure of exposure that integrated risk from sound and view of the aircraft. Exposure-response models for the characterization of effects consisted of behavioral thresholds in sound exposure level or maximum sound level units or slant distance. Available sound thresholds were limited for desert mule deer, but a distribution of slant-distance thresholds was available for ungulates. The risk characterization used a weight-of-evidence approach and concluded that risk to mule deer behavior from the Apache overflight is uncertain, but that no risk to mule deer abundance and reproduction is expected.     

Ecological Risk Assessment for Terrestrial Ecosystems: The Summary of Discussions and Recommendations from the Adelaide Workshop (April 2004)

The Ecological Risk Assessment (ERA) workshop focused on the anthropogenic contaminants in the terrestrial environment, addressing various components of the ERA process. These included sources, exposure pathways, bioavailability, and toxicity to receptor organisms as well as risk communication. It was concluded that although the overseas experience on ERA for terrestrial ecosystems (e.g., International Standards or guidelines from the European Union and the United States) is very useful, it is not directly applicable to Australia due to the differences in receptor organisms, contaminants, soil, and environmental conditions. Workshop discussions stressed on the need for making ERA locally relevant (in terms of choice of receptor organisms, sampling strategy, and bioavailability considerations). The workshop discussions highlighted the need of better appreciation of both the similarities and the clear differences between aquatic and terrestrial ERAs. The availability of reliable data, problems with databases, estimation of bioavailability, and extrapolations from laboratory to field were noted among the key limitations. ERA—being inherently complex and involving a range of environmental compartments, target receptor, and exposure pathways—at a minimum requires a multidisciplinary approach to address the complexities. Bringing a multidisciplinary team together often proves a major challenge in ERA. The delegates called for continued efforts in this area and formation of a network or working group in Australia.