Cell Signaling
Thousands of organic compounds are currently synthesized and released
into the environment, often with only a minimum of regulation and no clear
understanding of how chemicals interact with biological systems. The science
of environmental medicine is now acting fast to respond to the need for
such information by developing approaches to investigate these interactions.
Biologists are using advanced genetic and molecular tools, for example,
to define the pathway by which an individual cell is poisoned. This new
area of investigation, known as cell signaling, traces the interplay of
proteins within a cell from the instant the cell is stimulated from outside,
via its ion channels or membrane receptors, to the moment and method of
its destruction. Cell signaling is seen as the key to understanding how
basic cellular processes go awry in a variety of dysfunctions, including
cancer.
Neurotoxicologists are now using the principles of cell signaling formulated
by neurobiologists to study the fundamentals of environmental poisoning.
For example, scientists are just now understanding what happened in cases
of pesticide poisoning long assigned to the history books. One such event
was the "Ginger-Jake" case, in which about 20,000 Americans
were paralyzed in the 1920s from eating an extract of ginger called "Jamaica
Ginger" that had been treated with an organophosphorus ester.
This ester belongs to a class of pesticides that produce a syndrome known
as organophosphorus ester-induced delayed neurotoxicity (OPIDN), manifested
by paresis in the legs, hands, and thighs that occurs days to weeks after
exposure. In the later stages of OPIDN, symptoms of spinal cord injury such
as spasticity and ataxia become evident.
Investigators now know that the crucial biochemical journey these organophosphides
take starts at the cell's calcium channel, the protective gateway that limits
entry of calcium into the cell. Calcium is involved in the regulation of
a variety of nerve functions and is the ultimate target for many toxins;
the death of a cell is often associated with the cell's inability to exclude
calcium. Some toxins can also act by perturbing calcium signaling to the
point that cell growth is inappropriately favored.
The pesticide in the Ginger-Jake case directly affects a second messenger
in the signaling pathway known as calmodulin protein kinase II, an enzymatic
catalyst that phosphorylates a number of cytoskeletal proteins. A recent
experimental injection of an organophosphide in chickens resulted in such
increased phosphorylation that the nerve cells' neurotubules and neurofilaments
broke down and bound together. The result surprised researchers: they found
a jumble of nerve tangles of the type seen in such degenerative diseases
as Alzheimer's disease.
Research on cell signaling holds promise of unraveling the cellular basis
of a wide variety of neurodegenerative dysfunctions and other adverse health
effects that may be related to chemical exposure.
Volunteer Duty
Continuing a 36-year tradition, the Student Conservation Association
(SCA) sent some 1500 high school, college, and older individuals streaming
into 308 federal and state park sites nationwide last summer to learn about
resource management through hands-on conservation projects.
Avian answers. Volunteers at Mattamuskeet
National Wildlife Refuge in North Carolina study effects of mercury contamination
on ospreys.
More than 450 high school students worked on projects ranging from restoring
damaged areas of Clearwater National Forest in Idaho to maintaining and
repairing trails in Rocky Mountain National Park, Colorado. Approximately
1100 resource assistants, 18 years or older, worked as professional aides
with SCA's cooperating agencies on projects including backcountry patrols
in the Denali National Park and Preserve, Alaska, interpreting historical
sites such as Fredericksburg and Spotsville National Military Park, Virginia,
and monitoring wildlife and erosion control at Baxter State Park, Maine.
Volunteers logged about 700,000 hours of volunteer time in the nation's
parks this past season. In addition, the SCA also supported two international
volunteer programs between the United States, Mexico, and Canada.
The SCA was begun in 1957 from the idea that public lands offer a superb
training ground for individuals in conservation techniques of soil, water,
vegetation, and wildlife. The SCA works closely with federal agency partners:
the National Park Service, the U.S. Forest Service, the Bureau of Land Management,
and the U.S. Fish and Wildlife Service, among others. Foundations, corporations,
and other supporting organizations provide additional funding.
In addition to the high school and resource assistant programs, SCA sponsors
a program dedicated to bringing cultural diversity to the conservation workforce.
The Conservation Career Development Program (CCDP), funded by a grant from
the National Fish and Wildlife Foundation, seeks to broaden the conservation
arena by involving people within the context of their own cultures. According
to Cameron Bayne, a CCDP High School Component Supervisor, "Our environment
is diverse, and those who care for it should be as diverse."
Butadiene and Styrene Risks
Workers in plants that manufacture synthetic rubber and reinforced plastics
are being exposed to levels of butadiene and styrene gases thousands of
times greater than the general population, possibly correlating to greater
risk of cancers and other occupational health hazards.
Such was the evidence presented at an international symposium on "Health
Hazards of Butadiene and Styrene" held in Finland in April. More than
160 scientists from 17 countries attended the symposium, organized by the
Finnish Institute of Occupational Health and the International Agency for
Research on Cancer.
Regreening Yosemite. SCA's Conservation Career
Development program includes projects like revegetation of parks. John Goubeaux
The United States currently produces approximately 3 billion pounds a
year of butadiene, mainly for the production of synthetic rubber, and 9
billion pounds a year of styrene, used in plastics and products such as
Styrofoam. Though the general population may be exposed to these gases in
the air, cigarette smoke, water, or foods, the major concern of the symposium
was for workers in these industries whose exposures far exceed environmental
levels.
Current occupational exposure to butadiene in the United States is generally
less than 10 parts per million (ppm), with measured excursions as high as
374 ppm, compared to urban air concentrations of 1-10 parts per billion
(ppb). Although OSHA has proposed lowering the permissible occupational
exposure level to 2 ppm, this proposal has not been implemented, and the
level remains at 1000 ppm. Cancer risk estimates for workers exposed to
the proposed 2 ppm standard range from 0.2 per 10,000 workers to 600 per
10,000 workers, depending on the type of tumor.
Average exposures to styrene in polystyrene manufacturing plants are
less than 5 ppm. In the reinforced plastics industry, average concentrations
are 45 ppm, though peak concentrations may reach hundreds of parts per million.
Health risks to animals and humans from exposure to butadiene and styrene,
including genetic damage and cancer, were presented at the symposium. Epoxide
intermediates of butadiene were shown to cause gene mutations at both the
hprt and tk loci in human lymphoblastoid cells and at the
hprt locus in mouse splenic lymphocytes. Increases in chromosomal
damage in human lymphocytes were reported in a number of studies of workers
exposed to styrene; however, the dose-response relationships are not
clear.
Lung tumors have been induced in mice at the lowest concentration of
butadiene (6.25 ppm) ever used in a long-term study. Gene mutations in the
p53 tumor-suppressor gene, analogous to those found in a wide variety of
human cancers, were characterized in both lung and mammary gland tumors
in mice. Although no adequate inhalation studies have been reported for
styrene, gavage exposure to styrene oxide, a metabolite of styrene biotransformation,
caused forestomach tumors in rats and mice.
Epidemiology studies reveal associations between occupational exposure
to butadiene and deaths due to leukemias. A case-control study of leukemias
in plants that manufacture styrene and butadiene rubber showed a seven-
to ninefold increase in risk for workers exposed to butadiene, although
some believe the risk is actually much lower or nonexistent. Though no such
association was shown for styrene, small increased risks of leukemias and
lymphomas were reported in workers exposed to styrene in the reinforced
plastics industry.
Development of physiologically based pharmacokinetic models of the uptake,
tissue distribution, and metabolism of styrene and butadiene in the rat,
mouse, and human was presented at the symposium. Differences in internal
doses of mutagenic epoxides in rats and mice are too small to account for
the different carcinogenic effects of butadiene in these species. Discussions
also highlighted the need for more information on metabolism of these chemicals
in organs other than the liver and lung. There appear to be two groups among
the human population with different levels of sensitivity to the genotoxic
effects of these chemicals. More research is needed on the metabolic variability
of humans, particularly in susceptible populations. New markers of exposure
for butadiene and styrene were also presented at the conference, which scientists
hope may be useful for human biomonitoring and provide some of the much
needed information to evaluate human risks from exposure to these two chemicals.
Kids at Risk
Children may be at increased risk for effects of pesticides, a National
Academy of Sciences report concluded in July. The report cited deficiencies
in the way the government calculates safe levels of pesticides on foods
and its regulation of pesticides.
The NAS report, Pesticides in the Diets of Infants and Children,
states that children might be highly sensitive to pesticides on food and
that they consume 60 times more fruit than adults, leading to higher doses
of pesticides. "Older infants and young children may metabolize pesticides
more extensively and eliminate them more rapidly than adults," says
the report.
Some scientists, such as Jerry Taylor, director of natural resource studies
at the Cato Institute, disagree. In an editorial in the New York Times,
Taylor cited studies by EPA that found of 86,000 food samples, 81% contained
no pesticide residues. Taylor also questioned the practice of basing conclusions
on animal tests. "Given that animal laboratory tests have found half
of all natural chemical compounds to be carcinogenic, . . . one must question
why NRC or the federal government continues to rely on a practice that is
based on . . . assumptions," stated Taylor.
Nevertheless, federal agencies and the Clinton administration were quick
to react to the NAS report. Just before the report was released, three federal
agencies announced that they would work together to reduce the use of pesticides.
The White House issued a statement emphasizing its commitment "to reducing
the risks to people and the environment that are associated with pesticides."
Senator Patrick J. Leahy (D-Vermont), head of the Agriculture Committee,
said the Clinton administration was ready to reverse the policy of recent
decades and try to reduce the amount of pesticides used by farmers. Senator
Leahy said that because of the president's support, Congress may pass a
bill within the next year requiring alternative means of pest control such
as using beneficial insects or enriching the soil.
The two pesticide bills in Congress, one offered by Democrats and one
by Republicans, both would require EPA to calculate risks and permit pesticides
on the market only if they pose a negligible risk. The Democratic bill,
authored by Senator Edward Kennedy and Congressman Henry Waxman, defines
"negligible risk" as causing no more than one cancer or other
harmful effect per million people during a lifetime of exposure. The Republican
bill asks EPA to weigh the economic benefit of a pesticide against its health
risks.
The government now considers the amount of pesticide an "average"
person might ingest. The $1.1 million NAS report, which was requested by
Congress five years ago and was three years overdue, points out that risk
calculations do not consider pesticides from sources other than food, such
as drinking water and treatment of lawns and golf courses. "Pesticides
applied in legal amounts on the farm, and present in legal amounts on food,
can still lead to unsafe amounts," said Philip Landrigan, chair of
the committee that wrote the report.
Starting young.
Infant intake of pesticides on raw agricultural commodities far exceeds
the national average.
To improve understanding of how pesticides affect children, NAS urged
federal regulators to use immature animals to test toxicity, conduct food
consumption surveys for children, increase sampling of pesticides in foods
consumed by children, and consider all sources of exposure to pesticides.
Underwater Developments
Scientists will pump liquid oxygen to the bottom of Onondaga Lake in
Syracuse, New York, to determine how mercury and other toxic chemicals are
released from sediments.
An estimated 165,00 pounds of mercury was discharged into the lake by
Allied Chemical between 1946 and 1970. Some 7 million cubic yards of sediments
in Onondaga Lake are now contaminated with mercury. Fishing was banned in
the lake from 1970 to 1986, and the New York Health Department still warns
people not to eat fish caught in the five-mile-long lake or its tributaries.
Scientists will construct two corrals in the lake: one corral will have
oxygen added every other day; no oxygen will be added to the second one.
Water, fish, and plants will not enter the corrals during the experiment.
Crews have started constructing an elaborate pumping station to bring oxygen
to the lake's deepest point, about 60 feet below the surface. Researchers
will record changes in water chemistry by sampling water from a 25-foot
wide plastic tube extending from the surface to the bottom of the lake.
"We're really looking more at the water chemistry than anything
else," said Chandler Rowell, staff scientist for the Onondaga Lake
Management Conference. "It's basically to see if by adding oxygen to
the lake, you'll get any contamination from the sediments."
Scientists have theorized that a lack of oxygen at the bottom of lakes
plays a role in contamination, although they differ on whether the effect
of oxygen is positive or negative.
"Half the literature says mercury is released when there's no oxygen,"
said Jay Babin, a Canadian scientist involved in the experiment. "The
other half says it happens when there is oxygen.
The experiment will cost about $200,000 and is being paid for by a congressionally
established panel to devise and coordinate cleanup of the lake, which is
one of the nation's most polluted. The experiment will continue through
October.
On the Carpet
The stalemate between consumers who contend that their carpet is making
them sick and an industry which has long denied any evidence of carpet culpability
may soon be over. In a hearing June 11, the Georgia-based Carpet and Rug
Industry (CRI) told the House Government Operations Subcommittee on Environment,
Energy and Natural Resources that it would fund comprehensive health research
on carpet chemicals, including volatile organic chemicals, and consider
using labels to inform consumers of potential health effects.
EPA sources say the industry pledge defused a lot of the controversy
that arose from toxicology tests conducted last October by Anderson Laboratories,
Inc. of Dedham, Massachusetts. Results of those tests purported to demonstrate
that fumes from ordinary carpet can kill mice and may cause adverse health
effects in humans. However, both EPA and CRI attempts to replicate the tests
failed to produce the same results, and questions about differences in protocols
have been raised.
These tests were not the only impetus for the industry pledge. In 1991,
27 state attorney generals petitioned the Consumer Product Safety Commission
to require that information labels be affixed to carpet products and that
informational brochures be distributed at the point of sale. Industry has
now indicated it would consider voluntarily taking such action.
At the opening of the hearing, Chairman Mike Synar (D-Oklahoma) noted
that of EPA's $6 billion budget, funding for indoor air research receives
only $6 million, therefore making industry funding indispensable. Carpet
and rug manufacturing is an $8.5 billion-a-year industry. Although the exact
amount of industry funding has yet to be determined, Synar estimated the
cost to be $10 to $15 million over a three-year period.
CRI President Ron Van Gelderen said of Synar's estimate, "His guess
is as good as any. We are willing to commit resources but not in a direction
that is not validated by the scientific community." Steps toward such
validation will be taken by an interagency effort to set scientific objectives
for carpet research. Participating agencies would include the Occupational
Safety and Health Administration, EPA, the Consumer Product Safety Commission,
and the National Academy of Sciences.
Sustainable Development Council
President Clinton's creation of a broad-based presidential council on
sustainable development has been heralded as an opportunity for the administration
to forge alliances between those concerned mainly with economic growth and
those concerned with environmental protection. Clinton's council has been
contrasted to former Vice President Quayle's Council on Competitiveness,
which took a probusiness stance on the environment.
Industry sources welcomed the June 14 announcement as a sign of the administration's
committment to involving business interests in environmental decision-making.
Some environmental sources worried, however, that unlike Quayle's Council
on Competitiveness, this new council would lack influence in the development
of administrative policy. Others respond that this skepticism is unwarranted
for several reasons. First, Clinton's announcement came two weeks after
a national conference on sustainable development which recommended the establishment
of such a council, at which Vice President Gore strongly advocated strategies
for sustainable development. Second, the stature of many of the members
of the 25-member council virtually guarantee the council will receive the
president's attention on environmental policy decisions.
Members of the council, selected to form new coalitions between traditionally
divided constituencies, include Interior Secretary Bruce Babbitt, EPA Administrator
Carol Browner, Secretary of Commerce Ron Brown, Agriculture Secretary Mike
Espy, Energy Secretary Hazel O'Leary, and NAACP Executive Director Benjamin
Chavis. In addition to the five cabinet members, the council is made up
of eight representatives of industry, two of minorities, six of environmental
groups, one from labor, one state representative, and one philanthropist.
The council will be chaired by David Buzzelli, vice president and corporate
director of Environment, Health, Safety, and Public Affairs at Dow Chemical
Company, and Jonathon Lash, president of the World Resources Institute.
According to Lash and Buzzelli, the council's top priorities will include
global climate change and global standards for worker safety and health.
A plan of action by the council, noted Buzzelli, may be to "stand back
from issues of the day and take a broad perspective." The council will
meet four times a year for a two-year period.
Advancing Women's Health
"Why do women have poorer health outcomes?" asked Susan Blumenthal,
scientific director of the Society for the Advancement of Women's Health
Research at the society's 1993 scientific advisory meeting on the environment.
"It may be derived from adverse impacts of environmental factors such
as toxins in the atmosphere, drug exposures, or substances of abuse."
The meeting brought together leaders from medical and professional societies,
academia, and government such as the American College of Occupational and
Environmental Medicine, Columbia University School of Public Health, the
University of Texas/M.D. Anderson Cancer Center, EPA, and NIEHS. Consumer
advocate Ralph Nader and Congressman Henry Waxman (D-California), chair
of the House Subcommittee on Health and the Environment, delivered special
addresses.
Participants at the meeting focused on setting a research agenda to ascertain
links between health and environmental and social stressors. Discussion
called for more basic research at the biochemical, cellular, and molecular
levels in the context of physiological events. Menstruation, pregnancy,
childbirth, and menopause may influence the prediction of risks and outcomes.
"Disease is really the outcome of three factors--environment, both
internal and external, hormones, and microscopic elements in the cell,"
said John MacLachlan, scientific director of NIEHS, which co-sponsored the
meeting. "In the case of breast, cervical, and ovarian cancer, osteoporosis,
endometriosis, fibroids, and sexually transmitted diseases, we're . . .
still at the point where understanding the environment's role on any of
these disorders is a top priority and strategy from a research standpoint,"
MacLachlan said. "Diseases and dysfunctions associated with estrogens
that occur later in life raise the question of earlier exposures."
Ellen Silbergeld of the Environmental Defense Fund agreed. Silbergeld
said that bone is a major repository for lead that could resurface because
of changes in bone physiology and hormonal regulation of mineral metabolism,
particularly during menopause. "How our body handles lead is very complex,"
she said. "Ninety percent is absorbed into our bones." The question
according to Silbergeld is what is the impact, given that lead "may
be recirculated back into the body with potential toxic consequences."
Research recommendations from the meeting include educating public health
officials and physicians on precise human exposure assessment; setting standard
tracking techniques for pollutant exposures; establishing registries and
databases for breast implants and key epidemiological reporting with complete
health profiles; weighing the variable effects of fat and diet over a woman's
lifetime; devising new ways to measure clinical sensitivity; and accessing
findings of corporations, pharmaceutical companies, and medical specialty
societies.
Interagency monitoring of contaminant-induced illness was encouraged.
Participants also urged subprograms within the NIH Women's Health Initiative
to study the effects of environmental toxins on cancer, osteoporosis, and
endometriosis.
Last Update:August 21, 1998