Risk-Related Research at Lawrence Berkeley National Laboratory
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:
- Characterization of exposures of human populations to environmental
pollutants and radiation
- Development of the technical basis for setting priorities for
research and regulations by ranking possible hazards for occupational,
residential, and other settings
- Mechanisms of biological damage at the cellular, molecular, organ and
whole organism level, including development and validation of biomarkers
- Effects of environmental pollution on ecosystems and ecosystem
restoration
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.
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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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:
- A method for selecting chemicals to test in rodents based on an
index, Human Exposure/Rodent Toxicity or HERT, which prioritizes
chemical exposures
according to how they would rank in possible hazard if the chemicals were
rodent carcinogens. HERT uses readily available LD50 (lethal dose)
values instead of TD50 values of HERP.
- Estimation of a virtually safe dose from data on maximum tolerated
dose
- The validity of qualitative extrapolation between species is being
examined by comparing results on positivity of bioassays, target organ, and
carcinogenic potency between near-replicate tests,between different routes
of administration, and between
species for the known human carcinogens.
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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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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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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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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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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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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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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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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:
- Determining that the aquatic exposure pathway was the most
harmful to the wildlife
- Finding a simple way to eliminate the aquatic exposure pathway, i.e.,
drying the ponds, filling in low areas
- Demonstrating that naturally occurring bacteria protected the
underlying groundwater aquifer by immobilizing the selenium: and
- Convincing the regulatory community and environmental advocacy groups
of the appropriateness of this approach.
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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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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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,
[510]486-7491
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