Comprehensive Strategies Needed to Study Breast Cancer
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Breast cancer strikes one out of every nine women in the United States,
and there is evidence that these rates have been steadily increasing over
the last 20 years. Scientists are now taking a closer look at studies which
indicate that breast cancer is produced by a complex interaction of such
factors as hormonal status, genetic susceptibility, environmental exposures,
and dietary components.
Development of breast cancer. Rapid cell division (indicated by red staining) in the developing
mouse mammary gland enhances the potential for chemically induced mutations.
Richard DiAugustine. NIEHS. |
Results of several studies conducted by Japanese and American researchers
show that breast cancer rates in Japan are low (1 in 50), but rates in Japanese-American
women approach those present in the U.S. population, indicating that other
factors in addition to genetics play a part in whether a woman will develop
breast cancer. A study reported in the American Journal of Epidemiology
(volume 134, 1991) focusing on the effect of smoking on breast cancer rates
indicated that, although there does not appear to be an increased risk of
breast cancer in women who begin smoking as adults, breast cancer risks
are significantly elevated in women who begin smoking as teenagers. Similarly,
a study of atomic bomb survivors from Japan revealed that adult women exposed
to radiation had breast cancer rates similar to controls, but teenage girls
exposed to those same levels had markedly greater breast cancer rates later
in life. These findings suggest that susceptibility to cancer-promoting
environmental exposures may also be age dependent.
Animal studies bear out these findings as well. Thirty-two years ago,
a study by Nobel Prize winner Charles Huggins showed that administration
of polycyclic aromatic hydrocarbons (PAHs) to 50-day-old female rats produced
nearly a 100% incidence of mammary cancer, as opposed to a much lower incidence
in younger or older rats exposed to the same doses of these chemicals. PAHs
are found in urban air pollutants and cigarette contaminants. Scientists
believe that exposure to carcinogens during the period of rapid proliferation
of mammary cells during puberty may permit fixation of DNA damage in the
genome. Subsequent exposure to ovarian hormones, such as estradiol and progesterone,
which stimulate proliferation of normal breast cells, may also expand this
damage, resulting in the formation of breast tumors. Evidence shows that
the incidence of breast cancer is markedly reduced in women who have had
their ovaries removed before 35 years of age.
In addition to the interplay among environmental exposures, genetic susceptibility,
and hormonal factors, many scientists now add diet as a possible indicator
of risk for breast cancer. Although this contention is widely debated, some
studies have indicated a possible link between levels of dietary fat and
caloric intake and the incidence of breast cancer.
The catastrophic magnitude of breast cancer is compelling researchers
to develop research strategies aimed at understanding the integrated roles
of all of these factors in causing and promoting breast cancer so that effective
prevention and intervention approaches can be developed.
New EPA Administrator Enters Debate over Pesticide
Residues in Processed Foods
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Within two weeks of the confirmation of her appointment as administrator
of the Environmental Protection Agency, Carol M. Browner was faced with
difficult policy decisions regarding pesticide residues in processed foods.
The EPA administers the section of the Federal Food, Drug and Cosmetic
Act containing the "Delaney Clause" that prohibits any food substance
that contains any cancer-causing pesticide from being processed for human
consumption. The Delaney Clause was added to the Act in 1958 by the late
New York Congressman James Delaney after congressional investigation of
chemicals in foods and cosmetics. It was intended to protect consumers from
additional cancer risks presumed to result from consumption of contaminated
foods. The clause has remained in the Act ever since.
In the intervening years, analytic chemistry methods and techniques have
im-proved dramatically, and pesticide residues can now be detected at levels
below one part per trillion. At the same time, toxicologic studies have
been conducted that demonstrate some level of carcinogenic activity for
many agricultural chemicals. Under the Delaney Clause, no food products
containing any amount of a compound that has tested positive in any laboratory
study may be present in processed food. Many agricultural interests and
pesticide manufacturers argue that the Delaney Clause is too restrictive
and should be relaxed to permit very low levels of certain pesticides in
processed foods, particularly when the toxicologic evidence of carcinogenicity
from animal studies is equivocal or weak. The suggestion that "de
minimis" levels be established for such pesticides gained support
in a National Academy of Sciences report in 1989.
There is precedent for the de minimis approach. The Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) allows EPA to establish permissible
trace residues of chemicals that are carcinogenic in toxicologic studies
in nonprocessed, fresh produce marketed in the United States if the Agency
determines that they do not pose an unreasonable risk.
A majority of the members of Congress and the federal courts have not
been persuaded. Environmental groups and many public health experts note
that the scientific base for repeal or relaxation of the Delaney Clause
does not yet exist. They point out that very few pesticides have been completely
tested for the full range of possible health effects, and almost nothing
is known about the possible effects of consumption of the mixture of pesticide
residues that could result from a diet of different processed foods containing
different compounds. As a result, there is little enthusiasm in Congress
for allowing any more pesticide residues in foods.
Browner was brought into the controversy when EPA staff sent her a list
of 35 pesticides that EPA would ban under the Delaney Clause of the Food,
Drug and Cosmetic Act. In an article in the New York Times, Browner
was reported to support relaxing the Delaney Clause. However, she did release
the list of 35 pesticides, making clear her intention to comply with the
Delaney Clause. The ensuing publicity highlighted the controversy surrounding
the Delaney Clause and provided interest groups with an opportunity to restate
their views. Congress, however, is unlikely to intervene unless the new
administration takes aggressive action and submits a legislative proposal.
Such action on the part of the White House appears unlikely in the near
term given the many other pressing environmental matters on the legislative
agenda.
Congress and the Clinton Administration Move to Elevate
EPA to Cabinet Status
The failed Bush administration initiative to elevate the Environmental
Protection Agency to cabinet status was quickly revisited by President Clinton
and allies on Capitol Hill. In announcing his intention to appoint Carol
M. Browner as Administrator of EPA, the President stressed that she will
be treated as a member of the cabinet until his campaign pledge to make
EPA the newest federal executive department is realized.
Support from Congress followed immediately. Senator John Glenn (D-Ohio),
chair of the Senate Government Affairs Committee, was joined by 17 other
Sen-ators in submitting Senate Bill 171, the Department of the Environment
Act of 1993. In the House of Representatives, Congressman Sherwood Boehlert
(D-New York) submitted House Bill 109, which is identical to Glenn's proposal.
Before the submission of these bills, rumors of proposals for substantial
restructuring of the many agencies with environmental regulatory and research
programs had been circulating in the executive branch. These rumors fueled
speculation that either Clinton administration officials or Congress would
use the legislative process both to reorganize federal environmental programs
and to elevate EPA to cabinet status. Neither has occurred. The bills now
under consideration in Congress offer no substantive structural changes
in either EPA or the other federal departments or agencies. Quick action
on the bills is anticipated, and enactment seems assured given the wide
support for a Department of the Environment and the lack of controversy
in the proposals.
National Academy of Sciences Enters Controversy on
Relevance of Animal Toxicologic Studies
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The National Academy of Sciences Com-mittee on Risk Assessment Methodology
issued another of its series of reports on Issues in Risk Assessment
in February 1993. These reports have focused on the scientific methods used
by toxicologists in animal studies to test chemicals and other environmental
agents for adverse health effects. Such studies are critically important
in providing information for use by risk assessors in evaluating the hazards
to human health posed by exposure to these agents. The report focused on
the "maximally tolerated dose" in animal studies designed to identify
the capacity of the substance being tested to cause cancer in the animal
system.
The usual practice in such toxicologic studies is to determine the dose
of the substance to be studied that does not cause any acute health effects
in the test animals. This dose is then given in a continuous exposure regimen
to a group of healthy animals. In addition, other groups of animals are
exposed to the same substance but at lower levels to determine carcinogenic
potency and any dose response. These studies also include a group of animals
that are not exposed to the substance for use as a control. The rationale
for the use of the maximally tolerated dose includes the fact that the rodents
commonly used in toxicologic research metabolize chemicals at a much higher
rate than humans, and their life spans are much shorter than humans.
Some scientists believe that any carcinogenic effects noted in the group
of animals exposed to the maximally tolerated dose should be discounted
or ignored in extrapolating the results of the testing to humans in risk
assessments. They base their arguments on the premise that humans rarely
experience long-term exposures to environmental agents at levels as high
as the maximally tolerated doses established for toxicology studies and
offer hypotheses for mechanisms of carcinogenicity that are unique physiologic
re-sponses to very high levels of exposure.
The majority of the National Academy of Sciences committee recommended
the continued use of the maximally tolerated dose in the overall strategy
for toxicologic testing. The committee recommended that additional metabolic
and physiologic studies be conducted when the initial test results at the
maximally tolerated dose warrant further study. One-third of the panel disagreed:
They suggested that the metabolic and physiologic studies be conducted first,
and the dose regimens be established on the basis of the results of this
research.
The panel did agree on a number of matters. The scientists reported that
if a substance is a potent cancer-causing agent in animal studies, it is
likely to be toxic to people, and if the substance under test is carcinogenic
at relatively low doses in animals, it has a greater likelihood of being
a potent human toxicant. These points underscored the utility of toxicologic
tests to determine the maximally tolerated dose as preliminary screening
tests for the identification of potentially hazardous substances and the
prioritization of environmental agents for further toxicological studies.
The National Academy of Sciences will continue to study and report on
important issues in risk assessment. The report on issues surrounding the
maximally tolerated dose and associated recommendations for additional studies
of mechanisms of toxicity was issued with two other reports, one on the
two-stage model of carcinogenesis and the other on a new paradigm of ecologic
risk assessment.
Carnegie Commission Advocates Reorganization of Federal
Environmental Research Programs
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The Carnegie Commission on Science, Technology, and Government released
a report, Environmental Research and Development--Strengthening the Federal
Infrastructure, 15 December 1992. The report, drafted by a task force
of senior scientists and environmental policy experts with vast experience
within and outside government, called for substantial restructuring of the
federal environmental research and development organizations now found in
at least a dozen agencies and departments.
The report praised the scientists and engineers now working in the federal
system, but noted that they work in organizations that operate under priorities
and problems from the past and thus cannot address problems of today and
tomorrow. The Carnegie Commission called for reorganization and redirection
to come from the top of the executive branch through the appointment of
an individual in the White House with broad authority and leadership to
identify federal activities that support the environmental, development,
and risk reduction goals of the president. This recommendation seems to
have found fertile ground in the early plans of the Clinton administration:
the appointment of Kathleen McGinty (former Senate aide to Vice President
Gore) to head a newly created White House Office of Environ-mental Policy
was announced in early February.
The Carnegie Commission also provided many suggestions for improving
the environmental research and development programs in various departments
and agencies. One recommendation called for a new agency to conduct environmental
monitoring. It would build upon an organization created by combining the
National Oceanographic and Atmospheric Administration (now in the Department
of Commerce) with the U.S. Geologic Survey (in the Department of the Interior).
This new agency would be located in a new Department of the Environment
or established as an independent agency. The report also called for a National
Center for Environmental Information to consolidate and disseminate information
from the many federal environmental research and demonstration programs.
The research activities now managed by the EPA were discussed in detail
in the Carnegie Commission report. The commission suggested that the 12
existing laboratories of the EPA be consolidated into four major entities.
These would address ecologic systems; environmental monitoring systems;
environmental engineering; and health effects research. In addition, the
creation of at least six university-based "environmental research institutes"
was recommended. These institutes would offer flexible, problem-oriented,
multidisciplinary research capability in academic institutions across the
United States.
The recommendations for restructuring and reorganizing have not yet been
addressed by the Congress or the Clinton administration official. The first
two bills introduced in Congress to elevate the EPA to cabinet status did
not contain any substantial structural changes. Still, there will be hearings
on these bills at which testimony may be taken from members of the Carnegie
Commission Task Force that will provide ample opportunity to begin ex-ploring
these recommendations in detail and perhaps to begin implementing some of
the new changes advocated
Assessing the Risk Equation
Carrying out a mandate by Congress to make sense of federal risk assessment
and management techniques, the Environmental Protection Agency has convened
the Risk Assessment and Management Commission to examine these complex issues.
EPA says the 10-member commission, established under the Clean Air Act amendments
of 1990, will "direct a comprehensive investigation of federal decision-making,
including scientific, economic, and policy issues which arise in risk-management
decisions on cancer and other health problems."
This is not a scientific commission in the traditional sense, says Bernard
Goldstein, director of the Environmental and Occupational Health Sciences
Institute in Piscataway, New Jersey, and a member of the panel appointed
by the National Academy of Sciences. Goldstein pointed out that the members
of the panel have been selected from several different disciplines with
insight into risk assessment and management decisions. The commission's
"charge is very broad," Goldstein said. "I would hope that
there would be as much or more focus on risk management as on risk assessment.
To try to fix the problems in risk management by tinkering with risk assessment
is not the approach. There is a lot of intellectual challenge in risk management,
such as the 'bubble' approach. We haven't done as good as we should as a
whole."
Other members of the panel include presidential designees Thorne Auchter,
director and chief executive officer of the Institute for Regulatory Policy
and former head of the Occupational Safety and Health Administration; Barbara
Bankoff, president of Bankoff Associates of Wash-ington; and Anthony Thompson,
an attorney with the Washington law firm Perkins Cole.
Congressional appointees include John Doull, professor at the University
of Kansas Medical School, appointed by Senate Minority Leader Robert Dole
(R-Kansas); Virginia Weldon, a vice president at Monsanto Corporation, appointed
by House Minority Leader Robert Michel (R-Illinois), Joshua Lederberg, Nobel
Prize winner and former president of Rockefeller University, appointed by
House Speaker Thomas Foley (D-Washington), and Gilbert Omenn, Dean of the
School of Public Health and Community Medicine, the University of Washington
in Seattle, also appointed by Foley. The commission is required to publish
a draft report by May 1994 and submit a final report to Congress and the
president by November 1994.
Research Priorities for Mobile Air Toxics
The Health Effects Institute, a cooperative effort of the auto industry
and the EPA whose mission is to provide health effects information to ensure
that motor vehicle emissions do not pose unreasonable risks, recently undertook
a project to define priorities for research that would decrease uncertainties
in risk assessments for mobile air toxics. Under the 1990 amendments to
the Clean Air Act, Congress specified promulgation of regulations for motor
vehicles and fuels to control emissions of toxic air pollutants. Five compounds
or classes were designated as toxic air pollutants: benzene, acetaldehyde,
formaldehyde, 1,3-butadiene, and polycyclic organic matter. Regulation of
at least benzene and formaldehyde by 1995 is specified. Thus, there is considerable
urgency in identifying uncertainties in risk assessments for particular
compounds so that regulations may be directed toward those pollutants of
greatest health risk.
As a first step, HEI held a Mobile Air Toxics Workshop in Monterey, California,
4-6 December 1992. The workshop was organized and chaired by Bernard Gold-stein,
chair of HEI's Research Committee and director of the Environmental and
Occupational Health Sciences Institute. Co-chairs were Roger McClellan,
president of the Chemical Industry Institute of Toxicology, and Jack Moore,
president of the Institute for Evaluating Health Risks. Scientists from
academia, industry, and government worked to identify uncertainties in understanding
the potential risk of exposure to mobile air toxics, including methanol,
an important potential alternative fuel. Although cancer risk was the primary
concern regarding most compounds, there was also much discussion of noncancer
effects of potential importance. Participants discussed research priorities
for scientific issues that apply across all compound groups, such as dosimetry,
high-to-low dose extrapolation, exposure assessment, and molecular biology
approaches.
The HEI project is on a fast track to facilitate research funding efforts
by HEI and other research organizations and to provide research results
in time for consideration in developing regulations. A report titled Research
Priorities for Mobile Air Toxics is expected to be published by HEI
later this spring.
Clinton Cuts Council on Environmental Quality
President Clinton effectively abolished the Council on the Environmental
Quality on February 8, saying, "we face urgent environmental and economic
challenges that demand a new way of thinking and a new way of organizing
our efforts." Clinton has replaced CEQ with a new White House Office
of Environmental Policy.
Clinton named Kathleen McGinty, former aide to Vice President Gore, as
director of the new Office of Environmental Policy. Although former CEQ
chairpersons have enjoyed access to cabinet meetings, McGinty will have
the title of deputy assistant to the president, an executive office status
not normally included in cabinet sessions. This has some sources worried
that McGinty may lack the political clout to focus attention on environmental
issues. However, in announcing the new office, Clinton maintained that it
would "have broader influence and a more effective and focused mandate
to coordinate environmental policy" than the CEQ. McGinty will participate
"in each of the major policy councils: the National Security Council,
the National Economic Council, and the Domestic Policy Coun-cil, and work
closely with the relevant federal agencies," Clinton said.
The CEQ was established by the 1970 National Environmental Policy Act,
which requires government agencies to prepare environmental impact statements
for any project with potential environmental consequences. Along with oversight
of environmental impact statements, the CEQ has been responsible for an
annual environmental report. There is concern among many that the new, streamlined
office will be unable to handle these re-sponsibilities.
In an interview with Inside EPA, former CEQ chair Michael Deland
said the new office, expected to employ 10-15 staff members as compared
with the more than 30 employees of the CEQ, is a "comparatively low-level
and woefully understaffed entity." Jay Hair, president of the National
Wildlife Federation, has countered that "The CEQ had become weak, ineffective,
and virtually irrelevant under Presidents Bush and Reagan." In general,
reaction from environmentalists to the announcement of the new office has
been positive.
Sources say Clinton is preparing legislation to officially abolish the
CEQ. Past efforts to abolish the office by Presidents Carter and Reagan
were rejected by Congress, which has so far been supportive but reserved
regarding the new Office of Environmental Policy.
The Brain-Immune System Connection
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A number of findings have provided increasing evidence for an integrated
relationship among the nervous, endocrine, and immune systems. This relationship
was the focus of the PBS series "Healing and the Mind," by Bill
Moyers, which brought to the public's attention some ideas that scientists
are now beginning to explore in the laboratory. These ideas suggest that
such a relationship may influence diseases that in the past have been associated
with only one system.
The Brain-Immune System Connection. An environmental insult may influence the interaction between
the brain and the immune system. When an antigen enters the body, the immune
system begins to synthesize and release cytokines. Cytokines affect brain
function and activate the release of neurohormones, neuropeptides, and neurotransmitters
that influence immune function.Virginia Sanders, NIEHS
Scientists now propose that the environment may indirectly affect normal
immune function by directly affecting neuroendocrine or nervous system function;
the reverse may also be true. An example is immune dysfunction resulting
from a long-term, low-level exposure to environmental contaminants in the
workplace or at home. The precise role of such a relationship in the cause
or progression of disease states is not yet known.
Until recently, the nervous, endocrine, and immune systems have often
been researched as separate disciplines. However, researchers are now recognizing
that the models used to study response in one system alone are inadequate
for studying the response of a whole organism exposed to an environmental
insult. David Felten, professor of neurobiology and anatomy at the University
of Rochester and editor of Brain, Behavior and Immunity, is designing
and testing integrated models. According to Felten, "Autoimmune diseases,
such as lupus or rheumatoid arthritis, can be influenced by hormones and
neurotransmitters. [This influence may] perhaps provide insight into the
role that stressors or environmental insults may play in disease expression
or progression."
Research in this area is crucial to the development of potential therapeutic
approaches. Felten states, "Our investigations provide evidence for
direct connections between the brain and the immune system, with neurotransmitters
and neurohormones as important signals acting on receptors on cells in the
immune system. Altering such signaling by behavioral and pharmacological
interventions holds great promise for novel therapeutic interventions in
a wide range of immunologically mediated diseases and conditions."
Last Update: August 31, 1997