Editor's Note: This article is Part II of a three part series on the
use of animal and alternative models in toxicity testing.
We have come a long way since the days, early in the century, when Dr.
E.V. McCollum, to the amazement and consternation of his fellow Kansan farmers,
raided corncribs for mice and rats to use for nutrition experiments. McCollum
believed that it was essential to experiment with small animals with a short
life span. His rat colony, begun in 1908, was the first in the United States
to be used for nutritional investigations, resulting in information on the
importance of vitamins and other dietary elements. McCollum, were he alive
today, would likely be at the forefront of the movement to develop alternatives
to traditional animal models for experimentation and toxicity testing.
Technical improvements in tissue culture and the development of the Ames
test, which uses bacteria to detect mutagens, challenge the view that animal
testing is the only option in toxicity testing. In addition, there has been
a growing recognition of the limitations of certain standard in vivo
testing procedures. The explosion of knowledge in molecular biology has
also significantly affected toxicology. Moreover, the costs of assessing
potential health effects of some 200,000 substances per year that are newly
identified or synthesized necessitate alternatives to animal testing. It
has been estimated that the cost of testing a single substance using whole
animals is frequently in excess of $2 million. In addition, in vitro
testing provides the researcher with considerably more control of the variables
than whole-animal testing. However, the new tools for toxicity testing must
be looked on as adjuncts to traditional testing methods. Any testing method
has inherent difficulties: when using whole animals data must be extrapolated
from one species to another, and when using cell or tissue culture data
must be extrapolated to the whole organism.
The quest for alternatives to animal testing has been scientifically
driven, according to William Stokes, associate director for Animal and Alternative
Resources at NIEHS. New testing methods that more accurately assess hazards,
are less expensive and more rapidly determine toxicity are being sought
at NIEHS. It is the pursuit of these goals that account for the great progress
in alternative testing techniques. At the same time, certain basic tests,
such as the Ames test, continue to be the workhorses for specific areas
of toxicology.
Franklin Loew, dean of the Tufts Veterinary School, says it "became
clear in the early 70s, apart from the ethical, scientific, and technical
issues, that routine use of rats, mice, and guinea pigs in toxicology was
becoming increasingly expensive and time-consuming at the same time that
society wanted rapid answers. Issues like saccharin and bladder tumors drove
the work in this field toward a faster, cheaper, smarter system." Alternative
tests raise complex issues. If the standard two-year rodent carcinogen test
is accurate at the 90% level, is a two-week or two-month nonanimal test
using bacteria which is cheaper, quicker, and only 80% accurate acceptable?
The trade-offs of lower cost, speed, and increased accuracy are considered
respectable goals, according to Loew. Ultimately the question is one of
public policy.
History of Comparative Toxicology
Marcello Malpighi forecast in vitro toxicology when he wrote:
"The nature of things, enveloped in shadows, is revealed only by the
analogical method. Hence the necessity to follow it entirely ... to analyze
the most complex mechanisms by means of simpler ones." Malpighi went
on to describe his attraction to the investigation of insects and plants,
and mused that perhaps he should go even further, to study minerals and
elements in order to draw conclusions about the human organism.
Malpighi's contemporary, Anton van Leeuwenhoek, inspired by the glasses
used by drapers to inspect the quality of cloth, constructed the first microscope.
With his invention he investigated sexual reproduction and the transport
system of nutrients in plants and animals.
Experimental research based on sophisticated analytical procedures accelerated
in the early 20th century. Industrial toxicology has gained great importance
because of the expansion of industry, the growth of all branches of chemistry
(organic, food, medicinal) and the recognition of the rights of workers
to protection from possible hazards. Worker protection was brought forward
by a tenacious physician named Alice Hamilton who, in her autobiography
Exploring the Dangerous Trades, gave a graphic account of the history
of industrial toxicology in the United States.
Rex Burch and W.M.S. Russell's seminal work, The Principles of Humane
Experimental Technique, published in 1959, pointed the way to reducing
the number of animals used in research refining procedures by improving
the design and efficiency of testing and thereby reducing animal pain and
distress, and replacing whole animals with tissue cultures, microorganisms,
and other tools. This concept of reduction, refinement, and replacement
is now commonly referred to as the "three R's" of alternatives.
Though in vitro toxicology is a very young science and cannot replace
animal testing at this point, its potential is vast, and its current use
as an initial screen for in vivo testing is invaluable. In addition,
research into alternative models give us a better understanding of the whole
organism; data from human cell and tissue cultures may eventually be far
more accurate than data from other animal systems.
Perspectives
Alternatives to whole-animal testing include endpoint assays, cell and
tissue cultures, the use of tissue slices, toxicokinetic modeling, and structure-activity
relationships and databases. Some examples of nonwhole animal methods include
the use of bacteria and yeast to assess mutagenicity, chick embryos to assess
teratogenicity, and fixed enzyme systems to screen for bilogical effects.
Alan Goldberg, director of the Center for Alternatives to Animal Testing
at the Johns Hopkins University School of Hygiene and Public Health, says
that the main questions concerning the use of alternatives are 1) How do
we extrapolate from an in vitro system to an in vivo system
(i.e., how do we relate effects in single cells to complex interactions
in whole animals)? 2) How do we use available in vitro and in
vivo data to design better experimental approaches? and 3) How do we
predict potential biological effects from the chemical structure of a substance?
Concordance between results from alternative tests and those from mammals
is an important issue in protecting the public safety. It is also important
to note that research using cells, tissue cultures, or nonmammalian systems
is conducted not only as an alternative to using mammals but because a given
alternative system best answers the question under study. In vitro
studies also allow researchers to understand the discrete steps in a specific
sequence of events, which is difficult to do in whole animals.
Nonmammalian Models
In place of traditional animal models, nonmammalian vertebrates such
as fish, amphibians, reptiles and birds with certain characteristics in
common with mammals, are being studied. For instance, chemical transmisson
in nerve cells has been illuminated by study of the frog neuromuscular junction.
A central issue in the use of nontraditional animal models is how highly
conserved a particular organ or biological system is and therefore how well
a given system correlates with the human one. As Stokes, points out, "Where
you have highly conserved structures or mechanisms, you can use the lowest
phylogenetic organism or system, whether in tissue cultures or whole organisms
like the nematode to extrapolate to the human response." Stokes is
currently investigating the usefulness of the frog embryo teratogenesis
assay xenopus (FETAX) system. Fertilized frog eggs that develop into free-swimming
tadpoles in 96 hours are used to assess the teratogenic potential of chemicals.
Using a dissecting microscope, one can observe any perturbation in the development
of the embryo as it is exposed to known teratogens in a petri dish.
Mini labs. Teratogenic
effects of chemicals show up early and readily in transparent tadpoles.
The use of invertebrates, particularly insects, has provided fundamental
insights into living processes. Research on the eye pigmentation of Drosophila
led to the hypothesis that each gene controls a single enzyme, a concept
fundamental to modern molecular biology. The giant squid axon has provided
the basis for the concept of the ionic nature of the electrical action potential
in nerve transmission. Invertebrates with nervous systems biochemically
related to humans are commonly used for neurotoxicity tests. In a study
published in Cancer Research in 1988, Muller, et al. studied the
neurons of freshwater snails as a possible model for testing neurotoxic
side effects of antitumor agents.
Microorganisms are used as models in metabolism, genetics, and biochemistry
and can sometimes serve as models of more complex systems. For instance,
what is learned about mechanisms of gene expression may be applied to the
study of normal and pathological development of human embryos. It has been
shown that yeast has receptors for estrogen that appear to be identical
in affinity with those of the rat and human uterus.
One reason cell and tissue culture systems are valuable in toxicity testing
is that they can be observed with a light microscope while various components
of the system are manipulated. For instance, one can observe the beating
of cultured heart cells and note the effects of adding various chemicals
to the culture medium. Human oral fibroblasts are used for testing of dental
materials, and cell mats have been used for screening human tumors for sensitivity
to anticancer drugs.
Mathematical Models
Other in vitro systems and mathematical models are playing key
roles in the rapidly accumulating armory of alternatives. Intermediary metabolism
using synthesized biochemicals, reaction rates, and the role of catalysts
can be studied. Mathematical models can supplement and sometimes reduce
the number of biological studies necessary.
Melvin Andersen - In
vitro data make it possible to extrapolate to human
response. |
Melvin Andersen of the US EPA works with pharmacokinetic models to elucidate
processes at the molecular, biochemical, cellular, and organ system levels.
According to Andersen, such processes "determine the delivery of chemicals
to target tissues and the responses of tissues to the chemicals." Pharmacokinetic
models encode biological relationships in mathematical form and permit extrapolation
from high to low doses, from one species to another, and from one dose route
to another. These models also provide a method to extrapolate from relevant
parameters determined
in vitro to expected behavior
in vivo,
using quantitative data on tissue solubilities/ tissue binding, tissue-toxicant
interactions, rates of metabolism, and concentration response
in vitro.
Using in vitro data, it is possible not only to extrapolate to
human response but to look at the pharmacokinetics of other species, Andersen
notes "The ability to conduct interspecies extrapolations with physiological
models arises from the fact that these models are developed with a mechanistic
understanding of the factors which determine the disposition of a chemical."
Such models contain the critical biological determinants of uptake and disposition
of a given chemical. Andersen states that the "integration of these
determinants within the physiological structure permits scaling to any other
species of interest, including humans. The ability to account for differences
in the physiological and biochemical parameters among various biological
species with a physiological model reduces the need for conducting studies
in larger laboratory animal species to predict human dosimetry."
John Frazier - Dose-response
relationships are the core of toxicity testing. |
John M. Frazier, of the Division of Toxicological Sciences, at Johns Hopkins
University, addresses the issue of correspondence between
in vitro
and
in vivo dose-response relationships and the role of
in vitro
toxicity testing systems in the safety evaluation process. "The cornerstone
of any toxicological evaluation is the establishment of the dose-response
relationship which is used to predict the degree of biological response
expected under various levels of exposure. The objective is to identify
the most sensitive adverse biological response expected and determine a
safe level of exposure at which the probability of experiencing any adverse
effects is low enough to be acceptable to society," Frazier states.
The major components of the dose-response relationship are toxicokinetics
(all kinetic processes that determine the relationship between the exposure
dose and the delivered dose), initiation (the molecular reaction between
the active form of the toxicant and the molecular target), and toxicodynamics
(the sequence of events set off by initiation reactions at the molecular
level and cascading to higher levels of biological organization, culminating
in measurable effects).
In vitro systems have provided information on metabolic pathways
and mechanisms of action and have identified appropriate animal models for
extrapolating to humans. The in vitro system can serve as the "central
core of the toxiological process," says Frazier, providing information
about the initiation process as well as the molecular and cellular components
of the toxicodynamic phase. "The development of the scientific basis
of predictive toxicokinetics focused on physical-chemical properties, quantum
mechanical calculations, and in vitro measurements of metabolism."
Frazier points out that if human cells were used, species extrapolation
would be less important and only a minimal amount of animal study would
be needed to confirm in vitro findings.
Structure-Activity Studies
Herbert Rosenkranz of the Department of Environmental and Occupational
Health in the School of Public Health at University of Pittsburgh has been
involved for a number of years in nonanimal testing to predict health effects.
Rosenkvanz says that in order to go to the next step, a computer program
must be used.
Rosenkranz observes that often the importance of negative information
is overlooked: a "positive observation is important only against a
background of a mass of negative information," says Rosenkranz. For
example, in the field of toxicology, one tends to focus and report on carcinogens
and rarely asks what is the difference between the carcinogens and the noncarcinogens.
However, if one only looks at carcinogens, one may be driven into assigning
causality to a property, say electrophilicity, that seems to be prevalent
in these carcinogens. However, a more complete analysis may uncover the
fact that many noncarcinogens also exhibit that same property, thereby invalidating
the predictive value of this property."
The Computer Automated Structure Evaluation (CASE) program uses the difference
between active (biophores) and inactive (biophobes) molecules to identify
the factors that best discriminate between them. Rosenkranz uses a linguistic
analogy to illustrate this: to create a computer program with the capacity
to distinguish between words in English, German, or gibberish, "we
submit to the program a learning set consisting of a number of English words
and non-English words." Once read by the program, the word will be
"cut into pieces of three or more adjacent letters," creating
groups of lettters that can be identified as belonging to English, German,
or neither. "Once the program has digested the learning set and identified
the relevant attributes of the language, it can be challenged by a word
it has never encountered before and, as we do, try to classify the word
by the way it sounds. The CASE program follows such an algorithm to identify
the structural attributes of toxicity from a learning set of molecules of
known activity."
Other programs being developed include MULTICASE and the META program,
which can identify molecular sites susceptible to metabolic transformation.
Such programs are currently being used to evaluate the activity of diverse
molecules and the location of metabolic pathways to predict toxicity, and
the results show a high level of concordance with short-term assays.
A recent workshop held at NIEHS brought together some 200 scientists
and professionals to try to predict the outcomes of 44 rodent cancer bioassays
before the results of the studies were made known. Participants provided
overviews of their prediction methods and evaluated the strengths and weaknesses
of the methods. Strengths included success in predicting strongly carcinogenic
chemicals, the ability to ascertain classes of chemicals suitable for specific
tests, and the potential of all systems to be improved. Weaknesses included
a lack of understanding of the precise mechanisms of carcinogenicity and
the fact that most models used do not account for the multitude of differences
between rodents and humans.
Advances in molecular biology have increased the understanding of cellular
and molecular processes and the differences in these processes between humans
and animals. Tools from cellular and molecular biology are being used to
develop research strategies for identifying primary target genes. According
to William Greenlee, a dioxin researcher at Purdue University, the effect
of dioxin, through gene regulation, on growth and differentiation of human
skin can serve as a basis for "comparative studies with rat liver cells
where dioxin-dependent actions on growth and differentiation lead to tumor
production." Apart from understanding the relevance to humans of a
given response in rodents, biological mechanism-based approaches are needed
to determine if the most sensitive response in an animal model is necessarily
relevant to humans.
Thomas Sutter, a researcher at Johns Hopkins University, says that because
of the extensive knowledge of dioxin's mechanism of action, a biologically
based model for risk assessment that might eliminate some of the sources
of uncertainty in current risk estimates is being investigated. "The
dioxin risk reassessment provides a unique opportunity to demonstrate the
utility of human in vitro systems to generate mechanistically based, relevant
measurements of human dose-response relationships. Without improved sensitivity
of the methods of human epidemiology, or the incorporation of human in
vitro data into the risk characterization process, biologically based
risk assessments will simply represent improved models for the interpretation
of data generated by animal experimentation."
Challenges
As noted earlier, in vitro systems are generally less expensive,
require less time, and are more readily controlled. However, extrapolation
from cells and tissue cultures to the complex human organism is at best
difficult and, in terms of producing the complex physiological responses
of the whole organism, not likely at this point.
In assessing the risk presented by chemcials and drugs during embryonic
development. Barbara Hales of McGill University highlights the need for
a more in-depth understanding of physiological systems. Hales points out
that often it is the balance between metabolic activation and detoxification
that determines the toxicity of a drug or chemical and that little attention
has been paid to the role of detoxification pathways in the embryo in drug
teratogenicity. An essential understanding of basic mechanisms of normal
and abnormal development will increase our knowledge of the critical developmental
events such as the chemical messenger systems that may be the target of
teratogens.
Answers under glass.
Hamster embryo cell cultures provide clues to mechanisms of action.
One of the difficulties with cell cultures has to do with maintaining
differentiated cells. Cells in culture tend to become unspecialized after
a short time, losing the characteristics of the organ or tissue from which
they were taken. Immortalized cells that have been genetically altered could
prove useful for toxicity testing, though in in vitro testing one
looks for cells that respond closely to those of the intact human body.
Continuous cell lines have undergone extensive selection for the ability
to grow in culture, whereas normal cells have complex requirements for growth
and differentiation in culture. More than 200 specific cell types exist
in the human body. Adequate culture systems have been develped for only
a few of these cell types. The importance and great variety of growth factors,
cell regulators, and mediators must also be taken into account.
Conclusion
A wide array of new tools is now available for toxicity testing which
has the capacity to greatly increase our knowledge of the complex systems
under investigation. At the same time, there has not yet been a formal process
to organize, coordinate, or evaluate the validation and implementation of
advancements in in vitro testing. Validation resources suggested
in a report from the Johns Hopkins Center include a chemical bank, cell
and tissue banks, a data bank and reference laboratories, as well as the
formation of a scientific advisory board representing the academic, industrial,
and regulatory communities. The report states, "A framework capable
of fostering the validation of new methods is essential for the effective
transfer of new technological developments from the research laboratory
and into practical use."
Toxicology, previously considered an applied science, is now "a
symphony of all methodologies from many disciplines which attempts to protect
the environment, living organisms, and nonliving materials," notes
Goldberg. "We are entering a new era in which the rapidly accelerating
acquisition of knowledge from the revolution in molecular biology is directly
affecting toxicology research. The challenge is to weave this new knowledge
and technology into the fabric of toxicological research." Roger McClellan,
president of the Chemical Industry Institute of Toxicology, summarizes what
toxicologists and others consider most important: alternatives to traditional
animal models are not truly competing alternatives, but rather additional
means for attacking toxicology's perplexing problems. Says McClellan, "The
challenge is to use the knowledge and tools wisely as a complement to our
other approaches."
Myra Sklarew
Myra Sklarew is a freelance
writer in Bethesda, Maryland.
At the Midwest Research Institute in Kansas City, Missouri, Chief Scientist
Charles Graham exposes people to electric and magnetic fields, then tries
to make sense of their seemingly nonsensical physiological responses. "It's
a very curious thing," Graham says, pondering what is known thus far
about whether low-level electric and magnetic fields make people sick. "In
a sense, it's an incredible puzzle to solve, and many people are going at
it in different ways." Graham's work and other studies could ultimately
help solve the puzzle, revealing the relationship between people and the
invisible force that surrounds us -- the energy fields created by nonionizing
electromagnetic radiation. For now scientists must contend with uncertainty.
Like Alice in Wonderland, wandering through a surreal world of grinning
cats and finding it "curiouser and curiouser" Graham and others
investigating the possible health effects of nonionizing electromagnetic
radiation" (NIEMR) often find themselves in an uncharted world that's
full of surprises. In analyzing physiological responses to electric and
magnetic fields, contradictory findings are commonplace, says Russel J.
Reiter, professor of neuroendocrinology at the University of Texas Health
Science Center in San Antonio. "One feature that has characterized
this area of research is referred to as the 'Cheshire cat phenomenon',"
says Reiter. "That is, sometimes changes are seen, while in a similar
experiment the effects are less obvious or they disappear."
Public fears were first aroused by epidemiological studies that seemed
to link cancer with low-level electric and magnetic fields (often considered
in tandem, as EMF). Many investigators believe that only by understanding
biological responses to EMF can the puzzle be solved. Thus far, laboratory
studies have provided tantalizing clues. In Canada, M.A. Stuchly at the
University of Victoria reported last year that EMF can help promote tumors
in mice if the disease is first initiated and then co-promoted by a chemical
carcinogen.
Also under scrutiny are questions about how EMF might suppress the body's
production of melatonin, a hormone known to block tumor formation, at least
in vitro . Reiter says he has shown how DNA, can be damaged by free
radicals when melatonin levels are too low.
Meanwhile, researchers like W. Ross Adey of the Jerry L. Pettis Memorial
Veterans Administration Medical Center in Loma Linda, California, are examining
how cells communicate and how EMF could interfere with that process. Also
of interest is the relationship between EMF and calcium ions, which play
a crucial role in cell growth and function.
If It Can't Fry Him, It Can't Hurt Him
Electric and magnetic fields are a fact of life on earth. Noting that
we're constantly gripped by powerful natural fields, some researchers have
argued that man-made sources of such energy couldn't possibly do any damage.
But others contend that if high-level electromagnetic radiation can heal
bones, low-level exposure might also trigger dramatic (and potentially dangerous)
biological changes. Without a doubt, very high-frequency EM fields are hazardous.
X-rays, for example, are potent enough to fry living tissue and blast electrons
from atoms. Such ionizing radiation can clearly damage DNA, causing genetic
mutations and cancer.
At issue these days is whether nonionizing radiation which emit fields
too weak to break chemical bonds can damage human health. Included in the
broad category of nonionizing radiation are the extremely low-frequency
(ELF) fields associated with electric power lines, household appliances,
and a host of consumer products.
Higher on the electromagnetic spectrum, other forms of nonionizing radiation
are also common, from the radiowaves used to transmit radio and television
signals to the now-ubiquitous microwave oven. At microwave frequencies,
radiation still doesn't break chemical bonds, yet it is strong enough to
generate heat by vibrating molecules. White walls and doors block the electric
fields created by nonionizing radiation; magnetic fields travel straight
through most materials.
Until recently, says Adey, "engineers have taken the view that if
it cannot fry the subject, it cannot hurt him." Like many of his colleagues,
Adey takes strong exception to this line of thinking, since he believes
nonionizing radiation can indeed be dangerous, even at frequencies below
the tissue-heating level.
Not everyone agrees. More cautious sources from the U.S. EPA and the
National Academy of Sciences insist there's still not enough evidence of
a health hazard to take action. A 1992 report commissioned by the Committee
on Interagency Radiation Research and Policy Coordination under the Bush
administration found "no convincing evidence" that ELF fields
from household appliances, video display terminals, or power lines represent
a "demonstrable" health hazard.
Most recently, a committee of the National Research Council, the principal
operating agency of the National Academies of Sciences and Engineering,
concluded that a proposed nuclear-attack warning system operating at radio
frequencies would have "only a minimal, and probably undetectable,
impact on public health." However, the Research Council committee based
its risk assessment on studies of AM radio and microwave transmissions--not
the same frequencies to be used by the Ground-Wave Emergency Network (GWEN),
which was partially completed before Congress postponed further construction
in 1990 because of public concerns. There simply aren't enough studies at
GWEN frequencies to determine conclusively whether the system is safe, says
report committee chair Thomas. S. Tenforde, chief scientist with the Life
Sciences Center at Battelle Pacific Northwest Laboratories in Richland,
Washington.
Background: Epidemiology
Nancy Wertheimer - First
to show link between EMF exposure and childhood cancer |
In the late 1960s, the public grew uneasy as new, extra high-voltage power
lines were installed to handle increasing electricity demands. About the
same time, Soviet scientists reported neurological and other health problems
among switchyard workers exposed to high-voltage power lines. But many Western
scientists thought the Soviet research was flawed. Then, in 1979, Nancy
Wertheimer at the University of Colorado Health Sciences Center and physicist
Ed Leeper published a landmark study linking power-frequency fields with
the cancer deaths of 344 children in Denver. Based on estimated exposure
levels, Wertheimer and Leeper said children exposed to high EMF levels were
two to three times more likely to get sick than youngsters in less exposed
homes.
Though critics said the Wertheimer/Leeper study lacked proper controls,
it gained credibility when David Savitz virtually replicated the findings
in a far more meticulous look at 356 childhood cancer cases. The report
by Savitz, now a professor of epidemiology at the University of North Carolina
School of Public Health, said children subjected to high EMF levels (based
only on estimates of exposure) were 1.5 times more prone to develop cancer.
Since then, results of numerous epidemiological studies have shown a
statistical link between cancer and high EMF levels inside homes. Some studies
have also suggested a high incidence of cancer among electrical workers,
telephone linemen, and others exposed to high EMF levels at work.
Dimitrios Trichopoulos - Est-imates of EMF exposure give cause to doubt. |
Virtually all of the epidemiological evidence, however, may be called into
question by those who doubt the findings, such as Dimitrios Trichopoulos,
chair of epidemiology at the Harvard School of Public Health and an author
of the 1992 Committee on Interagency Radiation Research and Policy Coordination
report. According to Trichopoulos, most of the epidemiological studies are
statistically insignificant because they don't look at enough cases. Moreover,
Trichopoulos points out that epidemiologists have only linked health risks
to "surrogates" or estimates of EMF exposure, not to actual measurements.
When data are based on actual measurements, he says, epidemiologists typically
find little or no evidence of a health hazard.
Savitz contends that surrogates are, in fact, a more accurate measure
of what an individual has experienced over a period of time. "Sometimes
people think that a measurement taken today is the truth," he says.
"Well, it's the truth about what happened at that moment, but it's
an open-ended question as to whether it's the truth about what happened
10 years earlier."
Last year, two Swedish studies reported a link between cancer and EMF
exposure. The studies sent a ripple through the EMF research community because
some said they overcame weaknesses common to previous epidemiological work.
At the Karolinska Institute in Stockholm, for example, Anders Ahlbom and
Maria Feychting used detailed historical EMF-exposure records compiled by
the Swedish government. Such records are not available to U.S. researchers,
who must rely on crude estimates such as wire coding. Also, unlike most
previous epidemiological work, the Swedish studies seemed to show a relationship
between EMF exposure levels or "dose" and the subject's response.
Feychting and Ahlbom (whose widely distributed report has not yet been
published in a journal), evaluated various types of cancer among over 400,000
individuals who lived within 300 meters of high-voltage power lines at some
point during 1960 to 1985. Among this group, the researchers identified
142 children with various types of cancer as well as 548 adults with leukemia
or brain tumors. Based on exposure records, Feychting and Ahlbom determined
that youngsters subjected for long periods of time to 1 milligauss of radiation
were two times more likely to develop various cancers. At higher exposure
levels, cancer risks increased; children exposed to 3 milligausses were
four times more likely to get sick. (A "milligauss" is a measure
of magnetic field strength. According to the U.S. Environmental Protection
Agency, a person sitting one foot from a typical digital clock might be
exposed, on average, to 1 milligauss.) Among adults, Feychting and Ahlbom
found that those subjected to very strong fields were 1.7 times more likely
to get leukemia, though no link between exposure and brain cancer was found.
The researchers were unable to tie any of the cancer cases with actual measurements,
rather than estimates, of field strength.
The second Swedish study, led by Birgitta Floderus of the Natinal Institute
of Occupational Health in Solna, Sweden, showed that 104 men esposed to
high EMF levels on the job were more susceptible to chronic lymphocytic
leukemia. Floderus also found that health risks increased in relation to
exposure levels.
Trichopoulos wasn't impressed by the statistical significance of the
Swedish studies, nor by their use of exposure estimates. "I would be
inclined to take more seriously the evidence from epidemiological studies
if there were more biomedical evidence," he said.
Meanwhile, most epidemiologists admit that, no matter how meticulous
the study, it's impossible to account for all conceivable risk factors for
cancer, such as dietary habits or congested highways near homes.
Cellular Telephones
In the United States, electrical current alternates back and forth at
a rate of 60 Hertz or 60 cycles per second, powering everything from hair
dryers to television sets to clock radios and electric blankets. Everyone,
everywhere, is exposed to power-frequency fields.
Could everyday consumer products be dangerous? As scientists struggle
to answer this question, a deep chasm has developed between those convinced
of a risk and those who insist that the very idea is ridiculous.
Nationwide, the stakes are high. If low-level electric and magnetic fields
are found to be dangerous, utility companies might need to reroute power
lines, steering them clear of schools and homes. Keith Florig, an analyst
with Resources for the Future, a nonprofit research institute, , says the
United States could spend as much as $10 billion a year to minimize EMF
exposure if public fears are validated. Already, Congressman George Miller
(D-California) has proposed legislation to ban construction of new schools
or daycare centers in areas where EM levels exceed 2 milligauss (the gauss
is a measure of magneticfield strength.) And in San Diego, California, a
couple recently filed an ultimately unsuccessful lawsuit, claiming their
daughter developed kidney cancer because of nearby power lines.
Considering the public outcry over power lines, it's not surprising that
recent research has focused almost exclusively on power-frequency fields.
In recent years, far less research has addressed the effects of higher frequencies
within the nonionizing range such as radio and microwave frequencies. In
January of this year, the cellular telephone scare clearly underlined a
need for more research of higher-frequency nonionizing EM radiation effects.
Hand-held, portable cellular phones emit signals at levels of roughly 825
to 895 megahertz, a kind of no-man's land for research. Cellular phones
operate at frequencies millions of times higher than the 60-Hertz electric
lines that feed common household appliances and other consumer products
such as television sets.
The episode began when David Reynard went on CNN's "Larry King Live"
show, claiming his wife died of brain cancer caused by a portable-type cellular
telephone with a self-contained antenna. (No questions were raised about
the safety of household cordless phones, which operate at very low frequencies,
or permanently installed car phones with antennas mounted outside the vehicle.)
A national outcry ensued over the dangers of portable phone, although the
U.S. Food and Drug Administration said there's no evidence of a public health
hazard. "It is known that high levels of radiofrequency energy can
produce biological damage, and there is limited evidence that suggests that
lower levels might cause adverse health effects as well," the FDA said
in a news release. "However, there is no proof at this point that cellular
phones are harmful." In the same release the FDA hedged its bets, adding,
"We simply don't have enough information at this point to rule out
the possibility of a risk." The release went on to describe ways cellular-phone
users can minimize potential risks -- by keeping conversations short, or
by installing a car phone with a remote antenna. In response to concerns,
the Cellular Telecommunications Industry Association announced plans to
support further research.
Electric Blankets
Electric blankets have also been linked to increased cancer risks. In
another study by Wertheimer and Leeper, women who slept on electrically
heated beds had a higher than normal rate of miscarriage. Although Wortheimer
and Leeper attributed this finding to power-frequency EM fields, they were
careful not to rule out the possibility of effects of too much heat on fetal
growth.
According to Tenforde, chief scientist with the Life Sciences Center
at Battelle Pacific Northwest Laboratories in Richland, Washington, subsequent
studies of electric blanket use failed to show a consistent risk pattern.
Savitz demonstrated a "weak" link between childhood cancer and
the use of electric blankets, Tenforde says. But, he adds, another epidemiological
study found no connection between leukemia and electric blankets. In a report
by Bary Wilson, also of Battelle, electric blanket use was linked to changes
in melatonin, the possible anticancer hormone.
Epidemiologist Gerri Lee of the California Department of Health, Berkeley,
is currently analyzing data from a study of women who used electric blankets
and other bed-heating devices such as heating pads. Ultimately, she hopes
to learn whether the voltage, current, or heat generated by electric blankets
might contribute to miscarriages. In the face of scientific uncertainty,
Lee says, women concerned about a health risk should probably avoid electric
blankets, or at least use them conservatively.
Video Display Terminals
Few people in the United States can escape from the ever-present computer.
Since 1988, when M.K. Goldhaber reported an 80 percent rise in miscarriages
among women who used computer video display terminals (VDTs) more than 20
hours weekly, the public has repeatedly voiced concern about VDTs.
Goldhaber's findings were alarming. But in a recent review article, Tenforde
points out that Goldhaber's study failed to rule out other contributing
factors, such as job stress. Moreover, Lee says, Goldhaber collected his
data by calling women and asking them to recall their reproductive history
and computer use. "If you had a miscarriage, you might be more likely
to recall heavy computer use," says Lee, who is also conducting VDT
research.
Further, "nine other epidemiological surveys have not obtained evidence
for a significant elevation in spontaneous abortion rate or birth defects
as a result of prolonged exposure" to VDTs, according to Tenforde.
On the other hand, a Scandinavian study published in November 1992 said
women using VDTs that generated very strong magnetic fields within the extremely
low-frequency range were almost 3.5 times more likely to have miscarriages
than women using VDTs emitting weaker levels of such fields. Another report
from Australia linked an increased risk of brain cancer with VDT use.
Yet questions remain about exactly how to measure the fields generated
by VDTs, which seem to be unique. Computers run on electric current and
therefore generate power-frequency fields. They also emit fields at various
other frequencies within the kilohertz range. Lee is particularly interested
in VDT fields around 330 kilohertz. "That area is a very narrow band
and hardly any studies have been done to look at that," she says.
The VDT Health Foundation a collaborative effort of Apple Computer, Compaq
Computer, and the IBM Corporation, recently contributed $2.5 million to
establish a Center for VDT and Health Research at Johns Hopkins University.
Initially, one of the center's goals will be to establish clear-cut methods
for measuring and characterizing VDT fields, says Patrick Breysse, associate
director. The new center will provide grants for individual investigators,
Breysse says.
Radar Guns
After hearing more than 200 tragic stories of cancer among traffic cops,
Ohio State Highway Patrolman Gary P. Poynter is convinced that radar guns
are a health hazard.
Based on anecdotal reports, Poynter, who also serves as research officer
for the National Fraternal Order of Police, has assembled a database of
officers who used radar guns and developed various cancers, especially testicular
cancer. In testimony before a U.S. Senate subcommittee last year, Poynter
said officers seem to develop cancer in the region of the body most exposed
to radar. "Officers who used hand-held traffic radar were never told
not to place the radar gun between their legs," Poynter told lawmakers.
"After all, the industry standard said continuous exposure to this
type of device was safe...In Michigan, six officers in two small departments
developed testicular cancer. It has been estimated by some experts [that]
the rate of testicular cancer in this small cluster [is] seven times the
normal expected rate for testicular cancer for such a small number of officers."
Under the gun.
Car-mounted radar may help officers avoid testicular cancer. |
According to the FDA, traffic radar devices emit microwave radiation
at frequencies roughly 10,000 times lower than the levels inside microwave
ovens. "Although it is known that very high levels of microwave radiation
can be harmful, there is no firm experimental evidence at present that the
much lower levels of radiation emitted by traffic radar devices can be hazardous,"
the FDA said in its official release on the subject. Some animal studies
have tied biological changes to low-level radar, the release says, but no
one knows how humans respond to radar.
The National Institute for Occupational Safety and Health has investigated
the safety of radar guns as well as dielectric and industrial heaters. Common
in many factory settings, such heaters generate fields at frequencies similar
to radar-gun levels.
At least in laboratory animals, the NIOSH research has shown that "radiofrequency
fields can cause malformations and birth defects," says W. Gregory
Lotz, chief of the NIOSH radiation section. But, he adds, "The levels
that cause these effects are pretty high-- very strongly heating."
More recently, Lotz says, NIOSH-sponsored studies have focused on whether
radiofrequency exposure may have a synergistic effect on chemical carcinogens.
An example of this type of work was a 1991 report published in Teratology
by B.K. Nelson and colleagues. After exposing pregnant rats to a combination
of radiation and teratogenic chemicals known to cause birth defects, 100
percent of the litters included severely malformed pups -- a much higher
rate than predicted.
Another startling finding resulted from joint research by NIOSH and the
U.S. Army Medical Research Center. The Army wanted to find out whether the
lead in artillery shells could affect the reproductive health of artillery
personnel, Lotz explains. But when NIOSH examined a control group of radar
operators in the same company, he says, semen quality was lower among those
individuals.
The next step for research, Lotz says, is to find the threshold of exposure,
the point at which problems first appear. Until then, he adds, police officers
and workers operating industrial equipment generating radiofrequency fields
should heed exposure guidelines set by the Institute of Electrical and Electronics
Engineers (IEEE) and other professional organizations. While the FDA says
there's no cause for alarm, it also suggests some simple precautions that
could help minimize risks such as placing radar guns outside of vehicles
whenever possible.
Laboratory Observations
What do we know, based on laboratory observations, about how nonionizing
electromagnetic radiation could affect living organisms? Over the past two
decades, researchers have suggested that nonionizing radiation may indirectly
affect DNA, dull the body's immune system, alter levels of hormones such
as melatonin, or disturb the balance of calcium ions within cells. Studies
have also suggested a synergistic relationship between EMF and chemical
carcinogens. Larry Anderson, a staff scientist and program manager for Battelle,
notes that biological responses to EMF don't necessarily suggest a health
risk. "When people hear of biological effects, the tendency is to automatically
believe that it's a bad or a hazardous effect," Anderson says. "But
most of these observations of biological effects are within the normal range
from person to person, or even within one person from one moment to the
next."
Though EMF doesn't appear to damage DNA directly, researchers like Reba
Goodman of Columbia University have demonstrated that it can increase the
transcription of RNA. Exposure also seems to affect protein synthesis, a
critical step in cell development. Work by Adey and others has shown that
EM fields can affect the way calcium interacts with receptors on cell surfaces,
particularly within certain frequency windows. Calcium acts as a kind of
messenger, helping to carry signals from cell surfaces to the interior of
cells, where growth and metabolism are controlled. If calcium's function
is interrupted, Adey explains, growth enzymes may become more active, possibly
leading to uncontrolled cell proliferation and cancer.
Russel Reiter - Melatonin
may act as free radical scavenger. |
Bary Wilson of Battelle was the first to report a link between EMF and suppressed
melatonin production. Since then, Richard Stevens, also of Battelle, has
proposed a theory to explain how the combined effects of EMF and light at
night may promote breast cancer. Since melatonin is produced on a daily
light/dark cycle, with lower levels generated in the daytime, Stevens says
too much light entering the eye at night might block melatonin. Stevens
is currently working on a large study for the National Cancer Institute,
looking at EMF, light at night, and breast cancer.
Reduced melatonin could also suppress other hormones, Anderson says.
"If you reduce melatonin, you allow things like estrogen and prolactin
to increase," he says. "If you have increased estrogen you have
increased turnover of breast cells and increased opportunity for cancer."
It's important to remember, though, that while melatonin's anti-tumor function
has been demonstrated in the laboratory, its role in human beings is still
speculative.
Researchers are also taking a hard look at free radicals, the highly
reactive atoms liberated by broken chemical bonds. Under normal circumstances,
these atoms spin rapidly for only a fraction of a second before finding
a suitably charged partner. But if they don't find a partner, free radicals
can damage DNA, potentially causing cancer. Reiter believes melatonin helps
keep free radicals in check by acting as a potent free radical scavenger.
If the body's production of melatonin is suppressed -- by EMF exposure,
for example -- the hormone can't scavenge excess free radicals, and therefore
can't protect against DNA damage, he says. Reiter says his recent work with
animals shows melatonin to be 99 percent effective in protecting against
DNA damage by free radicals. "We think we have the mechanisms by which
melatonin is protecting DNA," he says. "Things are really falling
into place."
Current Research Directions
Every year, the U.S. government spends millions of dollars on nonionizing
electromagnetic radiation research. Additionally, the industry-supported
Electric Power Research Institute (EPRI) will fund $15 million of EMF research
this year, reports Stanley Sussman, EPRI program manager.
Recognizing the importance of such research, Congress earmarked $65 million
in 1992 for a 5-year effort to investigate the health effects of 60-Hertz
EM fields and disseminate research findings to the public. Authorized under
the 1992 National Energy Policy Act, the health effects research program
will be directed by the National Institute of Environmental Health Sciences
and the U.S. Department of Energy.
As of June, however, NIEHS had not yet received the promised funds. If
the money is delivered, it will probably be used to add an EMF component
to the large epidemiological studies already planned or underway, according
to Dan VanderMeer, NIEHS director of the office of program planning and
evaluation. "If there is a health effect from electric and magnetic
fields, it is a very weak effect," VanderMeer explains. "You would
need to study a very large group of people to identify those associations."
In addition, NIEHS would use Energy Act funds for animal studies and mechanistic
research at the cellular, subcellular, and intercellular levels. Such work
would complement existing NIEHS/NTP toxicology animal studies scheduled
to begin in September 1993, VanderMeer says.
Federal agencies say there's no evidence of significant health problems
from EMF. But they also say it may be prudent to avoid high EMF levels just
in case. After all, it's easy enough to move the clock radio away from the
bed, or keep a VDT at arm's length, or stand at least three feet from a
microwave oven while it's in use. Dave Kleffman, deputy director of the
EPA's Office of Health Research, questions whether so much anxiety is warranted.
"We're probably a lot better off looking at other risk factors, such
as smoking, diet, alcohol consumption, and seatbelt use," says Kleffman.
Still, many, like Louis Slesin, editor and publisher of Microwave News,
would rather be safe than sorry. When it comes to EMF, Slesin and would
prefer to err on the side of caution and hoping that, researchers may ultimately
discover that our fears were unwarranted.
Ginger Pinholster
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Last Update: August 26, 1998