Julie Wakefield
On the Chesapeake Bay off the bustling shores of Baltimore,
Maryland, "skip jacks," or "skippers" still fish the waters for the
area's famous oysters and crabs, toiling six days a week, from sunup
till sundown, much as their ancestors did centuries ago. Yet today,
these fishermen are telling researchers at the Johns Hopkins
University's Environmental Health Sciences Center (EHSC) a different
fish tale from the one their colonial forefathers might have told.
These fishermen have strikingly high rates of skin cancer. In an
ongoing study of about 800 fishermen, center researchers
determined that skippers have a 10-fold greater risk than the
general population of developing skin cancer. Among Baltimore-
based fishermen over the age of 70, the rate of nonmelanoma skin
cancers is 40%, reports Paul Strickland, director of occupational
health in the school's Department of Environmental Health Sciences.
This compares to a 4% prevalence rate in the general population.
Scientists believe the elevated numbers are mainly due to the
dramatic increase in life expectancy over the past century: the
fishermen are living longer, revealing the effects of a lifetime of
prolonged sun exposure.
The project is just one of many center-sponsored studies that looks
at various environmental and occupational exposures in populations
in Baltimore. Work at the center focuses on exposures to agents--
ranging from radon to chromium to semiconductor toxicants to dust
mite antigens--in populations from firemen to female telephone
workers.
In addition to its diverse industrial populations, Baltimore is a prime
test area for everyday urban exposures. For example, Baltimore
ranks sixth nationwide for ozone problems in cities. The Johns
Hopkins center has one of only a handful of academic inhalation
facilities in the nation. Lead exposure, in both inner city children and
adults, is another serious problem and is among the new research
directions of the Johns Hopkins center. In addition, Delaware,
Maryland, and the District of Columbia have some of the highest
overall cancer rates in the nation.
The Johns Hopkins center has made a name for itself for research in
biomarkers and molecular epidemiology, mechanistic toxicology, and
pulmonary pathophysiology. Center researchers seek to identify
environmental and occupational risk factors, early biological
indicators of disease, and biological and chemical markers of
exposure, in addition to understanding the mechanisms of
environmentally related disease, improving models of the effects of
pollutants, and developing interventions for reducing exposure risks.
The center's leaders are also putting an increased emphasis on
bringing the results of the center's research to the local community.
"We're trying to move it out faster than we did before. Previously,
we left it to the rest of the world to use research. Now outreach is a
criteria for performance of our center," explains Director Morton
Corn. Although the outreach program is still getting off the ground,
Johns Hopkins researchers are already working on a project with
Maryland Public Television to develop educational videos for
elementary schoolchildren on the environment, health, and how to
modify their lifestyles.
Philosophy and Focus
What really makes the center unique is its location in the Johns
Hopkins University School of Hygiene and Public Health, the oldest
and the largest public health school in the world, says Corn, who
became the center's director in 1991. Corn is carrying on the legacy
of the center's first director, Gareth Green, who helped bring an EHS
center to Johns Hopkins in the fall of 1985. The choice seemed to be a
natural, as Johns Hopkins maintains the largest department of
environmental health sciences in the country and the largest
environmental health science training program as well. The Johns
Hopkins center embraces a philosophical focus toward prevention
and protection that is characteristic of the way researchers think at
the school of public health, says Michael A. Trush, who became
deputy director in 1991. At the same time, the center is critical to
environmental health science at Johns Hopkins. "The idea of the
center is to make the whole more effective than the sum of its parts,"
says Corn.
For example, the center interfaces with the NIOSH Educational
Resource Center in Occupational Safety and Health, the nearby
Kennedy-Krieger Institute, the Johns Hopkins Center for Alternatives
to Animal Testing, and the Johns Hopkins Oncology Center. The School
of Hygiene and Public Health is composed of 10 departments, which
also adds to the opportunities for unusual collaborations and
linkages. There is a close interrelation between university research
and the NIEHS training program. The NIEHS training program is
currently training 20 predoctoral and 4 postdoctoral students at the
center through an NIEHS training grant.
Molecular markers in mold. Center researchers are studying moldy corn and peanuts which contain aflatoxin, a major risk factor for liver cancer in China. JHU-EHSC
Structure
The center has come a long way since Green founded it. In fact, the
organization is completely different from when the center was
started a decade ago, says James Yager, who coordinates the training
program. And it continues to evolve. The structure has mainly been
fine-tuned "to get greater synergy out of it," says Trush. "The center
structure and its core facilities are very, very important to
facilitating research and interactions."
The current structure of the center has evolved even during the past
five years to reflect the shifting emphasis of the center and to better
meet investigator needs and improve the quality and efficiency of
the research. About 67% of the center's $800,000 annual budget goes
into facilities to help attract scientists to the center. Center
researchers bring in about $16 million in grants per year.
Pilot projects are another new venture to attract researchers. The
Johns Hopkins center has $75,000 each year up for grabs, with
maximum awards of $12,000 each. In the past 4 years, the center
has awarded 28 pilot grants. Ten of these projects have been funded
at the national level.
There are four interlocking research programs: human exposure
assessment and molecular epidemiology, mechanisms of toxicity and
carcinogenesis, physiologic responses to inhaled pollutants, and
neurotoxicology. In 1991 and through part of 1994, the center had
six program areas. The human exposure assessment and molecular
epidemiology program combines two programs, the former
epidemiology and exposure assessment and the molecular dosimetry
and biological monitoring programs. The merger was made to better
integrate the research efforts in epidemiology, exposure assessment,
and biomarkers. In turn, the former environmental carcinogenesis
program was renamed the mechanisms of toxicity and carcinogenesis
program to reflect its changing research interests. And while the
name remains unchanged, the research focus of the neurotoxicology
program has become more mechanistic.
Ozone effects. Detection of monoclonal antibodies in the tracheal epithelium of mouse lung by the Cell and Tissue Analysis facility allows comparison of normal tissue (top) and tissue following a three-hour exposure to ozone (bottom). JHU-EHSC
Molecular Epidemiology
The human exposure assessment and molecular epidemiology
program, directed by John Groopman, brings together toxicologists,
epidemiologists, and environmental engineers to assess individual
risk from exposure to environmental and occupational agents.
One of the main thrusts of the program has been to develop
interventions to reduce the incidence of liver cancer in China.
Hepatocellular carcinoma, which is almost always fatal, causes more
than 250,000 deaths a year worldwide. Groopman and his colleague
Thomas Kensler have established the first clinical study of aflatoxin,
which is now under way in China. Aflatoxin is a mold contaminant of
food that has been implicated as a major risk factor for human liver
cancer in sub-Saharan Africa and China. The dietary parent
compound, called aflatoxin B1, is found in many foods and is
converted to its carcinogenic forms through metabolism by members
of the cytochrome P450 enzyme superfamily. The scientists have
studied the resulting metabolites, including two aflatoxin epoxides, to
determine how aflatoxins contribute to causing this disease. The
team found the first proof of aflatoxin's chemical-viral interaction.
Now they are following up that work with a chemopreventive
intervention for liver cancer with a drug called oltipraz. Later the
team plans to study how hepatitis B virus and other risk factors
affect aflatoxin biomarkers.
Toxicity and Carcinogenesis
The mechanisms of toxicity and carcinogenesis program is composed
of scientists whose research includes investigations on fundamental
mechanisms of toxicity and cellular processes. Understanding these
basic mechanisms is key for developing new exposure markers and
identifying cellular targets and susceptibility indicators.
Through a pilot grant, Yager, the program coordinator, and his
colleagues are looking into the effects of the altered metabolism of
endogenous estrogens, caused by environmental exposures to dioxins
and similar chemicals, on the oxidative DNA damage. The researchers
plan to determine whether the oxidative damage is site specific, and
possibly gene promoter specific, in the presence of the estrogen
receptor. Johns Hopkins researchers are also breaking ground in the
study of benzo[a]pyrene, benzene, dioxin, and dietary carcinogens.
Physiologic Responses to Inhaled Pollutants
The center's program on physiologic responses to inhaled pollutants,
directed by Wayne Mitzner, attempts to mimic real world breathing
conditions--just like those experienced if one were to take a walk
down a Baltimore street. For instance, people are not exposed to a
single agent at a time. In an urban setting there is heavy air
pollution made up of all kinds of volatile compounds. In addition, the
various agents may interact to produce additive or synergistic
effects. "It's almost like sucking on the tail pipe of a bus," says core
researcher George Jakab.
The program hopes to be able to investigate the entire spectrum of
questions that pertain to specific substances, from the quantitative
analysis of the exposure magnitude to a quantitative understanding
of basic pathophysiologic responses of cells and tissues to these
exposures. Plans are also in the works to expand the facility to study
volatile organic compounds and indoor air pollutants. This global
approach is fairly well developed for ozone, with studies spanning
from molecular genetics to human exposures.
A prime example of work in inhalation toxicology at the center is
Steven Kleeberger and Roy Levitt's work on the genetic influences on
resistance and susceptibility to environmental exposures. Their
current work involves comparing mice that are susceptible to
inhalation of ozone to mice that are resistant to characterize the
genetic control of the pulmonary response to ozone in mice. By
studying first- and second-generation mice, the team has identified
separate genes that regulate responses to acute and subchronic
exposures and derived a map assignment for those genes. Finding
human endpoints of ozone exposures is the next and ultimate step.
The scientists plan to begin addressing this question in the next year.
Neurotoxicology
The neurotoxicology program, headed by Tomas Guilarte, is evolving
to focus more on mechanistic studies. Lead neurotoxicity is the
program's primary area of research. A succimer intervention trial is
being conducted in local children through the Kennedy-Krieger
Institute. The multicenter clinical trial is the first human trial of
succimer, a chemical shown to chelate lead and bring down blood
lead levels in laboratory animals. Researchers are testing the efficacy
of succimer in chelating or binding lead and removing it from the
bodies of children who have high concentrations of lead in their
bloodstreams.
Guilarte is studying the role of the NMDA (N-methyl-d-aspartate)
receptor in learning and memory deficits found in experimental
animals and humans who were exposed to lead during development.
Scientists have demonstrated that NMDA receptor activation is
essential for the induction of use-dependent physiologic processes
such as long-term potentiation--a cellular model of learning and
memory. Guilarte's work seeks to delineate how lead inactivates the
NMDA receptor complex and to characterize the effects of lead
exposures on the development and regulation of the NMDA receptor.
Paul Strickland and his colleague Brian Schwartz are trying to
determine whether there is a link between plasma delta-
aminolevulinic acid (ALA) and blood lead levels in children and
whether ALA is a good biomarker of lead exposure.
Aside from state-of-the-art research and provocative new
approaches to environmental health science, what really drives the
center's work is the commitment that the center and the Johns
Hopkins University School of Hygiene and Public Health have made
to the citizens of Baltimore and the surrounding areas to help create
a healthy living environment. "That's the way we think," Yager says.
Brain lead. Qualitative autoradiography
shows low (blue) and high (red) levels of binding to the NMDA
receptor of the hippocampus in rats exposed to lead during gestation
and lactation. JHU-EHSC
The National Toxicology Program presented eight technical reports at
a public review by the NTP's Board of Scientific Counselors on June
20-21 at the NIEHS. These reports included a predictive analysis of
potential noncarcinogenicity based on metabolism, six standard
studies characterizing the toxicology and carcinogenicity of selected
chemicals, and a comparison study of the effects of limiting food
consumption or body weights on carcinogenesis evaluations.
1,4-Butanediol. The NCI nominated 1,4-butanediol for study
because of its high volume production as a chemical intermediate
and potential for worker exposure. 1,4-Butanediol metabolizes
rapidly to gamma-hydroxybutyric acid, which is also the end metabolite of gamma-butyrolactone. Because the NTP has already performed a full toxicology and carcinogenesis study of gamma-butyrolactone and found no
effects at any doses, it was possible to predict that 1,4-butanediol
would similarly not be carcinogenic in animals.
Codeine. Codeine is used in a variety of pharmaceuticals as an
analgesic, sedative, and antitussive agent and is one of the most
frequently prescribed therapeutic drugs in the United States. In two-
year studies, rats and mice were given codeine in the feed at doses
ranging from 10 to 100 times the human prescription doses (on a
dose per body weight basis). There was no evidence of
carcinogenicity of codeine in these studies.
1,2-Dihydro-2,2,4-trimethylquinoline. 1,2-Dihydro-2,2,4-
trimethylquinoline is used in the preparation of antioxidants for
butadiene-based rubbers and latexes. In two-year studies, the
chemical (in acetone solution) was applied five times per week to the
skin of rats and mice. Male rats exhibited an increased incidence of
kidney neoplasms, indicating some evidence of carcinogenic activity.
There was no evidence of carcinogenicity in female rats or in either
sex of mice.
Butyl benzyl phthalate. Butyl benzyl phthalate is used as a
plasticizer in a variety of synthetic polymers. In a mating study,
exposure to butyl benzyl phthalate in the feed for 10 weeks
produced marked effects on male reproductive parameters, including
decreased testis, epididymis, and seminiferous tubule weights, and
dramatically decreased sperm production. In two-year studies, male
rats exhibited some evidence of carcinogenic activity based on an
increase incidence of neoplasms of the pancreas. There was equivocal
evidence of carcinogenic activity in female rats based on the
occurrence of a few uncommon neoplasms in the pancreas and
urinary bladder.
Salicylazosulfapyridine. Salicylazosulfapyridine (SASP) is used
in the treatment of ulcerative colitis and Crohn's disease. When given
in the feed for two years, SASP caused liver tumors in male and
female mice, which was interpreted as clear evidence of carcinogenic
activity. In rats, SASP caused the formation of calculi and
proteinaceous concretions in the urinary bladder, extensive urinary
bladder hyperplasia, and some papillomas, which were interpreted
as some evidence of carcinogenic activity.
t-Butylhydroquinone. t-Butylhydroquinone is an antioxidant
used in cosmetics and meat products. It was not carcinogenic in rats
or mice when given in the feed for two years.
Scopolamine hydrobromide trihydrate. Scopolamine
hydrobromide trihydrate is the active ingredient in transdermal
patches for motion sickness and is also used in ophthalmic
preparations. It was not carcinogenic in rats or mice when given in
water by oral gavage for two years.
Diet Restriction Studies
Studies of butyl benzyl phthalate, SASP, t-butylhydroquinone, and
scopolamine hydrobromide trihydrate each included additional
groups of animals that were used to compare the standard NTP
bioassay protocol, in which animals are given access to feed ad
libitum, with protocols where the amount of food consumed was
restricted. Comparisons were made between the tumor incidences in
animals exposed to chemical with their normal controls and with
controls that had diets restricted such that their body weights
matched the exposed animals. Other comparisons were made where
control animals and exposed animals received approximately 20%
less feed than animals eating unrestricted amounts.
In general, animals with lower body weights or those receiving less
food had lower incidences of neoplasms at several sites. The
sensitivity of the bioassay to detect carcinogenic responses was
affected by dietary restriction: when dosed animals in the ad libitum
protocol were compared with controls that had similar body weights,
the significance of the tumor incidences was greater. However, some
effects observed in the normal ad libitum protocol were not
reproduced when control and dosed animals were subject to dietary
restriction. The relations between reduced body weights and lower
incidences of neoplasms also illustrated the importance of dose
selection in design of long-term animal studies, in which doses higher
than the "minimally toxic dose" might result in lower body weights
and complicate comparisons with concurrent control groups.
J.
Carl Barrett, chief of the NIEHS Laboratory of Molecular
Carcinogenesis that was part of the team that isolated the breast
cancer susceptibility gene, has been named Scientific Director of the
NIEHS. As Scientific Director, Barrett will assume leadership of 700
scientists and support personnel in 18 laboratories and branches
ranging from molecular biology to applied toxicology and clinical
research.
Barrett was chosen after a competitive national search, in part,
because of his contributions to research on the multiple steps of the
cancer process, the mechanisms of environmental carcinogens such
as asbestos and hormones, the relationship between cellular aging
and cancer, and the identification of the genes involved in human
cancers. In May, Barrett and colleagues at the NIEHS identified a
gene that suppresses the spread of prostate cancer and that may
provide a marker for prostate cancers that metastasize.
In announcing the appointment, NIEHS Director Kenneth Olden noted,
"Dr. Barrett has stimulated great excitement within the scientific
community with his laboratory's achievements. Scientists within the
institute cannot help but benefit from his example and leadership as
we advance into the next century."
Barrett received a bachelor's degree in chemistry at The College of
William and Mary in 1969 and a doctorate in biophysical chemistry
from The Johns Hopkins University in 1974. After a three-year
postdoctoral fellowship at Johns Hopkins, he joined NIEHS in 1977.
Barrett has authored or co-authored 265 scientific publications and
is an adjunct professor at the University of North Carolina at Chapel
Hill in the departments of pathology, epidemiology, toxicology, and
genetics and molecular biology. He is also an adjunct senior fellow in
the Center for the Study of Aging and Human Development at Duke
University Medical Center.
James R. Fouts, a scientist who has spent more than 40
years at the frontier of the development of toxicology and
environmental health as scientific disciplines, has retired as Senior
Scientific Advisor to the director of the NIEHS. Fouts joined the NIEHS
as a senior scientist in 1970 and served until his retirement on the
institute's executive committee. "The science that Dr. Fouts did here,
the scientists that he trained here and around the nation and the
world, and his creative contributions to programs will have a lasting
impact for the future," said NIEHS Director Kenneth Olden.
During his years of scientific research, Fouts's expansive range of
interests have included mammalian and marine drug-metabolizing
enzyme systems; comparative pharmacology and drug metabolism;
the pharmacology of antimetabolites and antibiotics; drug-chemical
interactions; preclinical drug testing; and pharmacogenetics. Fouts is 1 of 57 pharmacologists to be named
to the "1000 Contemporary Scientists Most-Cited 1965-1978," by
Current Contents, an indication of the fundamental impact of his
research to the research of others.
Fouts received a bachelor's degree with highest honors in chemistry
at Northwestern University, where he was appointed a tutorial fellow
in biochemistry. He earned his doctorate in biochemistry and
pharmacology at Northwestern University and later worked at
Burroughs Wellcome Research Laboratories in Tuckahoe, New York,
under Nobel Laureate George Hitchings. In 1957, Fouts joined the
faculty of the Department of Pharmacology in the College of Medicine
at the University of Iowa, where he also served as director of the
Oakdale Toxicology Center.
A touchstone throughout his career has been Fouts's enthusiasm for
training young scientists. Over the years he has trained 19
postdoctoral students and 17 graduate students, including senior
scientists at the NIEHS, and has served as an informal mentor and
teacher to many others.
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