Risk-Related Research at Lawrence Berkeley National Laboratory

Table of Contents

  • Human Exposure Assessment
  • Cancer Risk Assessment
  • Extrapolation of Cancer Risks from Animals to Humans
  • Biodosimetry to Assess Human Genotoxicity from Mutagenic or Clastogenic Agents
  • Transgenic Mouse Models
  • Biological Effects of Complex Chemical Mixtures
  • Physiologically-Based Pharmacokinetic (PBPK) and Cancer Models
  • Electromagnetic Fields
  • Risks of Ionizing Radiation in Space
  • Risk-Based Remediation Strategy for Kesterson Reservoir
  • Wetland Restoration and Sediment Quality
  • Integrated, Risk-Based Environmental Clean-up
  • SELECT: Environmental Decision-Making Software
  • Introduction

    The Ernest Orlando Lawrence Berkeley National Laboratory (LBNL) conducts research to improve the scientific basis of risk assessment.

    Scientific knowledge developed in the research is then integrated by multi-disciplinary teams to develop more effective and less costly risk management strategies for solving environmental problems. Research is focused in several major areas to support these overall goals:

    Efforts are made to understand and to relate the full sequence of exposure, dose, metabolisms, early and late indicators of effect and adverse impacts on humans and ecosystems.

    Human Exposure Assessment

    LBNL conducts integrated research on total human exposure to environmental pollutants and radon, with an emphasis on the indoor environment. The indoor environment and human activities in that environment are major determinants of exposures to many pollutants and to radiation because of the time spent in this environment -- 90 percent on average. In addition, concentrations of many air pollutants are higher in indoor than outdoor environments (e.g, radon, volatile organic compounds) because of the presence of indoor sources and the low air exchange rates of buildings relative to the outdoor environment. The transport and photochemical transformation of outdoor pollutants are also investigated and provide a basis for total exposure assessment.

    Biologically-relevant exposure metrics, for complex chemical mixtures, are developed which can be related to both carcinogenic and non-carcinogenic health effects. Total human exposure and health risk are examined in an integrated framework to establish the relative significance of various categories of pollutants and to focus research efforts. Models are developed to estimate the distributions of population exposures for various pollutants. Methods, technologies and policies to reduce pollutant exposures and risks are evaluated for effectiveness.

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    Cancer Risk Assessment

    LBNL researchers are developing strategies for setting research and regulatory priorities that can improve methods of risk assessment. We broaden the perspective on human exposures by ranking possible carcinogenic hazards to humans from many sources including natural chemicals in the diet. Our results challenge many assumptions of regulatory policy designed to reduce human cancer.

    Our analyses are based on animal cancer tests on 1228 chemicals in our Carcinogenic Potency Database. Possible carcinogenic hazards are ranked on an index, HERP (Human Exposure/Rodent Potency), that expresses each human exposure (daily lifetime dose in mg/kg body weight) as a percentage of the rodent TD50 (tumorigenic dose for 50% of the animals, in mg/kg/day). HERP values are compared to synthetic chemicals in indoor and outdoor air, workplace air, water, drugs and food to those for chemicals that occur naturally as food constituents or from cooking food. Our ranking indicates that carcinogenic hazards from air and water pollution or from pesticide residues are likely to be of minimal concern relative to the background of natural substances. Several issues in risk assessment methodology are currently being addressed:

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    Extrapolation of Cancer Risks from Animals to Humans

    Our ability to extrapolate cancer risks from animal experiments conducted at high doses to humans, typically exposed to doses that are orders of magnitude lower, requires understanding the details of the metabolism of a chemical and its molecular mechanism of interaction at the target site. LBNL conducts research to understand the molecular mechanisms of initiation of related carcinogens and their common metabolites. Vinyl chloride is currently being investigated. Over 3 billion kg/yr of vinyl chloride (VC) are produced in the U.S. VC has been amply documented as a human carcinogen associated with liver haemoangiosarcoma and tumors of the brain and lungs. No mechanism for its tumorigenicity has emerged, even though tumors are easily induced in rodents, and VC and its mutagenic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), have been intensively studied.

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    Biodosimetry to Assess Human Genotoxicity from Mutagenic or Clastogenic Agents

    Two biological assays performed on individual human blood samples are being developed for assessment of the mutagenic effects from exposure to ionizing radiation or to genotoxic chemicals. These assays measure early effects of exposure that are associated with a potential risk of late effects such as cancer development. One measures the frequency of a class of peripheral blood erythrocytes which express gene loss phenotypes caused by mutational events that occur in the erythroid progenitors found in each individual's bone marrow. The second measures the frequency of peripheral blood lymphocytes which contain balanced translocations in the mitotic cell chromosomes. Human lymphocytes in peripheral blood are abundant and accessible. In addition, many lymphoid cells are very long-lived and can provide an integration of exposures to genotoxic agents over extended periods, e.g. decades.

    The bioanalytical methods are being used in a prospective epidemiology of a subpopulation of humans which appears to be more sensitive to genotoxic effects. The methods also are being automated for rapid and inexpensive completion. With such improvements, it should be feasible to monitor or screen populations in high risk occupations, and/or environments to give early indicators of potential long term health dangers. Additional research is underway to develop a more rapid and safer method for chromosome analysis of DNA-damaging agents.

    A general goal of this research is to incorporate results of these analytical techniques into risk estimation algorithms designed to predict the risk of cancer development in individuals based on estimates of their genotoxicity susceptibility factors as well as their accumulated lifetime exposure to mutagenic or clastogenic phenomena.

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    Transgenic Mouse Models

    Radical-mediated oxidations have been implicated in the development of numerous chronic and degenerative diseases, including cancer and atherosclerotic heart disease. Exposures to ionizing radiation and to many environmental chemicals, including ozone, can cause oxidative damage in biological systems. A breeding colony of transgenic mice, with altered resistance to radiation-/chemical-induced damage due to overexpression of genes which are suggested to inhibit oxidative disease mechanisms, has been established. These genes have been introduced into C57B1/6 (atherosclerosis-susceptible) mice, and thus, their effects can be measured in terms of susceptibility to therosclerosis as a prototypic disease endpoint associated with oxidant stress. Oxidative injury to tissues and acceleration of atherosclerosis in fat-fed C57B1/6 mice by ionizing radiation and selected chemical oxidants are being investigated in this transgenic mouse model. Future environmental toxicology studies, based on the introduction of other genes, are anticipated.

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    Biological Effects of Complex Chemical Mixtures

    Complex chemical mixtures produced by combustion for energy production and other purposes are ubiquitous in the environment -- in air, water and soils. The genotoxic and non-genotoxic effects of such mixtures are not well understood despite their significance to human health and the environment. LBNL research on complex mixtures is directed toward understanding the effects of mixtures at the molecular, cellular and whole organ level and the relationship of effects to chemical composition and physical state.

    Normal human epithelial cells are being used as one system for investigation of chemical mixtures. More than 80 percent of all human cancers are of epithelial origin and these cells have the capacity to convert inactive chemicals to their biologically active forms. The genotoxic effects of compounds are determined by monitoring DNA adduct formation by the 32P-postlabeling method and induction of aromatic hydrocarbon the cytochrome P450 monooxygenase enzyme system, a non-genotoxic effect.

    The lung is the primary target organ for the many airborne toxic agents, including particulate matter, to which the population is exposed. At the interface between air and blood in the alveolar region of the lung, a thin liquid layer of surfactant floating on an aqueous subphase prevents the alveoli from collapsing. Perturbations of this lining layer accompany many pulmonary diseases such as emphysema, pulmonary edema, pneumonia and respiratory distress syndrome. Little is known about this fluid compartment and its response to combustion products such as motor vehicle exhaust and tobacco smoke. New technology developed at LBNL employs an x-ray microprobe in conjunction with the Low-Temperature Electron Microscope which permits measurement of potassium, chlorine and sodium concentrations in individual cells and samples of the alveolar lining layer in response to inhaled materials and in lungs deprived of oxygen. The effects of various complex mixtures on the lung, including the assessment of effects of acute and long-term exposures on the integrity of cellular and vascular compartments, and the effect on surface tension along the airways, are being investigated. This research will advance understanding of the mechanisms by which the health endpoints are effected.

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    Physiologically-Based Pharmacokinetic (PBPK) and Cancer Models

    PBPK models are developed to describe the distributions of toxic environmental chemicals, such as benzene, pentachlorophenol, pesticides, and their metabolites, inside the body. These models are being used increasingly in risk assessment to allow interdose, interspecies and interroute extrapolations as well as estimations of target tissue doses. The PBPK models developed at LBNL treat physiological model parameters as random variables within the constraints of empirically observed distributions. The effects of model parameter uncertainties on risk estimates are then analyzed using Monte Carlo simulations. Interindividual variability is readily incorporated so that this simulation approach lends itself well to describing distributions of the risk for the population.

    A model of carcinogenesis based on computer simulations has been developed and is being refined as new research findings on the process of carcinogenesis emerge. The model integrates DNA repair, cell-to-cell interactions, cell differentiation, and both point and chromosomal damage (mitotic recombination). Because the essence of the simulation technique is probabilistic, the model can be used to describe both intra- and interindividual aspects of population heterogeneity and individual susceptibility. It is expected that this approach will ultimately lead to improved risk assessment modeling for extrapolations to the low level exposures experienced by most of the population.

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    Electromagnetic Fields

    LBNL conducts research on electromagnetic fields which is directed at identifying the biological response of cells to electromagnetic fields and the underlying biophysical basis of such interactions.

    Additional investigations target ELF (extremely low frequency) fields associated with electricity distribution systems and appliances, microwave fields associated with developing telecommunication systems, and high intensity NMR/MRI fields used in clinical diagnostic procedures.

    An important focus of this recent work has been the development of unique exposure systems for performing cellular studies during exposure to very well-defined electromagnetic fields. Studies are being carried out with one of these systems to determine if human breast cancer cell growth is influenced by environmental level magnetic fields. Preliminary results indicate that magnetic fields influence breast cancer by blocking melatonin oncostatic function. The possible role of estrogen receptor in this interaction is being investigated.

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    Risks of Ionizing Radiation in Space

    One of the many hazards which must be considered for long-duration manned exploratory missions in space is the exposure of astronauts to ionizing radiations. The risks evaluated include the effects of acute exposures to protons and the effects of low-fluence exposure to near-relativistic heavy charged particles. In the latter case, the endpoint of concern is the risk of induction of heritable genetic alterations. Stable genetic alterations such as point mutations, partial gene deletions, and allele loss have been shown to be an important component in the process of carcinogenesis. Quantitative information has been assembled on the risk of mutation induction in a sensitive human cell line following exposure to a series of accelerated protons and iron ion particles, which are representative of the major sources of astronaut exposure to ionizing radiation.

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    Risk-Based Remediation Strategy for Kesterson Reservoir

    The remediation strategy developed for the Kesterson Reservoir is an example of the LBNL's multi-disciplinary approach to integrating scientific understanding into environmental remediation. In 1983, the Kesterson Reservoir in California's Central Valley became the focus of national attention when dozens of birds were killed by exposure to hazardous levels of selenium in agricultural drainage water. A team of LBNL chemists, hydrologists, soil scientists and aquatic ecologists developed a risk-based remediation strategy that, when implemented in 1988, reduced the cost of remediation from an estimated $150 million to less than $10 million. Keys to this successful strategy were:

    Risk assessment models that combined reactive chemical transport in the subsurface with food web analysis were used to support the remediation strategy. Since completing the Kesterson project, the LBNL research team has worked on related projects throughout the Central Valley of California, and at the Stillwater Marsh in Nevada.

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    Wetland Restoration and Sediment Quality

    Advanced tools of ecological risk assessment are being developed and incorporated into environmental remediation and ecosystem restoration at contaminated sites. LBNL researchers have assessed the sublethal effects of environmental contamination on aquatic ecosystems and have recently expanded their efforts to include wetland toxicology and restoration. Techniques have been developed for testing the toxicity of sediments in San Francisco Bay and there has been extensive work with multi-agency groups to develop new and practical approaches for ecological risk assessment. At present, there are no standards for sediment protection. Thus, research is needed to provide a strong scientific basis for standards and protective measures for aquatic sediments.

    Work is also in progress to develop genotoxicity testing techniques for aquatic ecosystems, some of which could lead to patentable products. The results of a recent study on the efficacy of treatment of toxics in storm water runoff for San Francisco Bay wetlands can be used as an integral part of marsh restoration design and engineering. A multi-institutional wetland consortium is currently being organized to provide scientifically-based guidance for the remediation of contaminated wetlands associated with defense sites slated for closure.

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    Integrated, Risk-Based Environmental Clean-up

    An interdisciplinary team of scientists and engineers at LBNL is developing a user-friendly, PC-based methodology and software for evaluating and comparing environmental remediation technologies with respect to their cost-effectiveness and risk reduction. The software will build upon and integrate existing codes for various sub-components of the methodology, e.g., sub-surface transport of contaminants, advection of contaminated soil gases into buildings, HERP tables for chemicals of concern. Crucial to the development of this methodology are more realistic analyses of human exposure and health effects, as well as more objective evaluation of the effectiveness of characterization and remediation technologies. The project currently involves collaboration with McClellan Air Force Base and a small business but is expected to expand to include collaborators at other DOE national laboratories and industries.

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    For more information, contact:

    Joan M. Daisey,
    Lawrence Berkeley National Laboratory,

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