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American Journal of Epidemiology
Copyright © 1996 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Vol. 144, No. 8 (Suppl)
Printed in U.S.A.
Cancer, Environmental Health, and Birth Defects-Examples of New
Directions in Public Health Practice
Godfrey P. Oakley, Jr. 1 and Clark W. Heath, Jr. 2
INTRODUCTION
Principles and opportunities
When it was first established in 1949, the Communicable Disease Center (CDC) was designed as a national agency for controlling infectious diseases. The
evolution of the CDC to its present status as the
Centers for Disease Control and Prevention, with public health responsibilities for all forms of preventable
or controllable disease, infectious or not, reflects the
work and vision of many public health leaders over the
years.
Perhaps more than most, Alexander D. Langmuir
played a pivotal role in this evolving process. While
true to his principal assignment, to build lasting competency in infectious disease epidemiology at the
CDC, he always welcomed opportunities to extend the
principles of epidemiologic research and investigation
to noninfectious disease areas. Eventually this willingness to practice epidemiology broadly led, in the mid1960s, to the establishment of epidemiologic programs
at the CDC which were concerned with cancer, birth
defects, and family planning. Those early ventures into
fields of noninfectious disease epidemiology provided
the foundation for the CDC's National Center for
Environmental Health, National Center for Chronic
Disease Prevention and Health Promotion, and for the
Agency for Toxic Substances and Disease Registry.
This chapter is an account of those early Langmuir-led
ventures into noninfectious disease epidemiology,
with particular emphasis on the subsequent growth of
CDC programs in cancer, environmental health, and
birth-defect epidemiology.
It is not certain that such programs, or at least their
epidemiologic roots, would have developed as they
did were it not for Langmuir's vision of epidemiology
and for the exploratory spirit of the CDC's early days.
Although firmly grounded in the mainstream infectious disease epidemiology of his day, Langmuir
viewed epidemiology both as the central scientific
discipline of public health and as an intellectual research tool with wide biologic relevance for understanding all human ailments. He was able to think
broadly about epidemiologic applications and to envision approaches well beyond what was accepted contemporary practice within the CDC's early mandate
for communicable disease control. It was the combination of these qualities with Langmuir's pragmatic
approach to real world public health opportunities that
enabled his extraordinary success in extending the
CDC's epidemiologic reach during his 20-year career
with the agency. Beyond the mere fact that Langmuir
joined the CDC at its start when opportunities for
shaping new programs were greatest, he recognized
the need to conduct epidemiologic research while responding to requests for practical epidemiologic assistance from state and local public health departments.
Teaching of chronic disease epidemiology
An important aspect of epidemiologic work at the
CDC has always been the practical instruction in
epidemiologic techniques which Epidemic Intelligence Service officers receive as they begin their
assignments. From the beginning of the Epidemic Intelligence Service program, Langmuir regularly included chronic diseases in the teaching curriculum,
although the necessary emphasis was on infectious
diseases. Teaching exercises included at least one noninfectious disease problem (usually Goldberger's classic studies of pellagra). Often, Langmuir enlisted
teaching expertise from chronic disease epidemiologists at the National Cancer Institute, the Johns
Hopkins University, or the University of Michigan to
help with the regular Epidemic Intelligence Service
Accepted for publication April 9, 1996.
Abbreviation: CDC, Centers for Disease Control and Prevention;
DDT, dichlorodiphenyltrichloroethane; MACDP, Metropolitan Atlanta Congenital Defects Program; PBB, polybrominated biphenyl;
TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.
1 Division of Birth Defects and Developmental Disabilities, National Center for Environmental Health, Centers for Disease Control
and Prevention, Atlanta, GA.
2American Cancer Society, Atlanta, GA.
Reprint requests to Dr. Godfrey Oakley, Centers for Disease
Control and Prevention, 4770 Buford Highway (F34), Atlanta, GA
30341-3724.
858
Cancer, Environmental Health, and Birth Defects
course or to give special courses devoted to noninfectious or chronic diseases.
As the CDC's own experience grew in these areas of
epidemiology, this aspect of epidemiology instruction
was increasingly conducted by the CDC's own chronic
disease staff. In the early 1970s, a manual of analytic
epidemiology principles was produced, together with
exercises based on classic studies of cigarette smoking
and chronic diseases. Thereafter, further chronic disease exercises were devised using the CDC's own
field investigations as topics for instruction. These
included the vinyl chloride-hepatic angiosarcoma experience (1), the ionizing radiation and leukemia cluster studies in Utah and Arizona (2), polybrominated
biphenyl (PBB) exposure in Michigan (3), acute parathion poisoning in Jamaica (4), and dichlorodiphenyltrichloroethane (DDT) exposure in Triana, Alabama
(5). The use of such exercises, taught mostly by the
CDC epidemiologists who themselves had directed the
field studies, sustained the tradition of practical training in epidemiology that Langmuir emphasized as a
fundamental strategy for maintaining epidemiologic
excellence at the CDC.
CANCER
Cancer clusters
A major point of entry for the CDC into public
health areas involving cancer, and eventually environmental health, was through field epidemiologic investigations of so-called cancer clusters in local communities. Such investigations often arise in response to
requests from state health departments for epidemiologic assistance when faced with reports of apparent
increases in cancer case occurrence in local communities.
The earliest of these cancer cluster studies, undertaken with Langmuir's encouragement, occurred in the
mid-1950s. The topic, however, did not attract substantial attention until the 1961-1962 study of eight
cases of childhood leukemia in Niles, Illinois (6). That
study, conducted by the CDC in cooperation with the
Cook County Health Department and the National
Cancer Institute, focused principally on the idea that
unusual infectious disease patterns might underlie observed local increases in leukemia frequency. This
infection hypothesis was suggested in the Niles situation by the concentration of most cases (seven of
eight) in families using a particular parochial elementary school and by a bimodal time pattern of case
occurrence that paralleled a similar pattern of
rheumatic-like illness in the school. A subsequent
community-wide survey sought information about
time patterns for common childhood illnesses (meaAm J Epidemiol
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sles, mumps, chicken pox) according to family groupings by church and school attendance. While some
similarity in time occurrence was seen with varicella
occurrence in the parochial school group, no conclusions could be drawn.
It was speculated at the time that, since the affected
community was newly established (5 years earlier the
area had been open farmland), perhaps the sudden
mixing of new families, drawn to a newly built community from many different older communities, might
bring with it a mixing of imported infectious disease
patterns among children. The result might be this
transient appearance of increased leukemia occurrence
as an aberrant response to childhood infections.
It is interesting that this same hypothesis regarding
an infection-related origin for childhood leukemia has
recently been entertained in the United Kingdom,
some 30 years after the CDC study in Illinois. As an
outgrowth of attention focused on a cluster of five
cases of childhood leukemia in a small town that had
been newly established to support the employment
needs of a nearby nuclear fuel reprocessing plant (7),
a series of epidemiologic analyses have strongly suggested that rates of childhood leukemia may be distinctly increased in so-called "new town" settings,
whatever the social or economic impetus for such new
population groupings (8).
Birth defects and cancer
One further aspect of the Niles leukemia study deserves notice since it indirectly influenced later events
at the CDC, again encouraged by Langmuir, whereby
the epidemiology of birth defects came to receive
parallel attention with cancer. Review of childhood
death certificates for the Niles community during the
time period of leukemia excess revealed an unusual
number of deaths attributed to severe malformations,
and, in particular, to different forms of congenital
heart disease (6), an observation which invited speculation about possible diverse postinfection disease
sequelae.
The idea was reinforced a year later when a CDC
field study of a childhood leukemia cluster in the town
of Orange, Texas, found evidence of a similar excess
in fatal congenital heart disease cases (9).
These observations, coupled with knowledge concerning biologic relations between leukemia and
Down's syndrome (l0, 11), and with the advent of
chromosomal analysis in humans, provided the rationale for Langmuir's support in 1965 for a leukemia
epidemiology unit at the CDC that included a cytogenetics laboratory and soon grew to encompass birth
defect epidemiology. This unit established surveillance for leukemia and Down's syndrome in metro-
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Oakley and Heath
politan Atlanta, Georgia, and, with the help of other
new cytogenetics laboratories in the area, linked cytogenetic studies with cases. Soon thereafter, the Metropolitan Atlanta Chromosome Group was founded,
later evolving into the Metropolitan Atlanta Congenital Defects Program (MACDP) as Down's syndrome
surveillance expanded to include all birth defects diagnosed in the first year of life. An Atlanta study
subsequently addressed the frequency of childhood
cancers among infants with birth defects (12). The
birth defects program at the CDC is described in more
detail later in this presentation.
Oncogenic infection
When the CDC leukemia epidemiology unit was
established in 1965, much of its work was supported
through a cooperative agreement with the National
Cancer Institute because of its strong interest in conducting oncovirus studies as part of cancer case-cluster
investigations. At that time, substantial progress had
been made in identifying animal cancer viruses, especially those associated with leukemia and lymphoma
in rodents, cats, and cattle, and there was considerable
hope that similar work would be successful in studies
of human leukemia. The National Cancer Institute's
support continued for more than a decade, during
which time a wide range of community case clusters
were studied, the majority focused on childhood
cancer (13). This work included occasional case
groupings of tumors associated with the Epstein-Barr
virus (e.g., nasopharyngeal carcinoma (14) and
Burkitt's tumor), as well as studies of persons in
contact with animals affected by leukemiallymphoma
or infected with leukemogenic virus (cats, cows, monkeys). Several other investigations focused on families
in which multiple cases of leukemia or lymphoma had
occurred. In some of this work, virologic studies were
coupled with immunologic testing (15). Although no
specific infectious agents were identified, these investigations established a useful foundation for later more
successful efforts.
At the same time, various statistical studies were
conducted to assess the extent to which cases of leukemia, especially among children, might generally
occur in time-space clusters. Like similar analyses
elsewhere (16), this work showed, at most, only a
slight tendency for clusters to occur beyond the frequency that is predictable by random case distribution
(17, 18). It was recognized, however, that such statistical assessments of case clustering tendencies can
only offer a sense of the probability that any particular
case grouping mayor may not be due to chance. They,
therefore, have only limited value in judging the possible biologic significance of any given case cluster. It
was also recognized that the rarity of case clustering
(beyond random expectation) could not be taken as
evidence against a possible infectious etiology for
leukemia or other cancers, since known infectious
diseases in which most infection is subclinical are not
characterized by time-space case clustering.
In the course of such studies, reports appeared of
apparent cancer case clusters in which people with
leukemia or lymphoma seemed linked, not in time and
place, but by acquaintance networks such as a network
of high school classmates who developed Hodgkin's
disease years after they graduated (19). Several instances of such acquaintance clustering were studied
in the course of the CDCIN ational Cancer Institute
collaboration, but with negative results. As with other
statistical studies elsewhere, an assessment of leukemia or lymphoma frequencies among high school
classmates in Connecticut yielded no evidence that
cases tended to cluster (20).
ENVIRONMENTAL HEALTH
Although epidemiologic studies of cancer conducted at the CDC focused principally on hypotheses
of infectious causation, environmental exposures also
received attention, especially from the early 1970s on.
Such work, actively encouraged by Langmuir, encompassed questions of exposure to radiation as well as
exposure to potentially toxic substances.
Ionizing radiation
The first environmentally oriented field study involved a CDC veterinary consultation in 1953 concerning skin lesions and increased mortality among
sheep grazing along the western Utah/eastern Nevada
border. This problem was eventually traced to radioactive fallout from atmospheric nuclear tests (2). In
1962, the CDC took part in an investigation concerning an apparent excess of leukemia cases in Washing"
ton and Iron Counties in southwestern Utah. Similar
case cluster studies were undertaken in the mid-1960s
in four different towns in southern Utah and northern
Arizona. In all instances, there was concern that radioactive fallout might have played an etiologic role.
While reconstructed dose estimates for the region suggested some increased cancer risk from radiation (21),
no clear explanation for the particular local case concentrations was ever established (2). Most of the leukemia clusters that were investigated in Utah were
identified through a case-surveillance program set up
by the CDC in the mid-1960s to assist in the early
identification of such apparent case concentrations.
Similar surveillance projects, conceived in the spirit of
Langmuir's concepts of public health surveillance,
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Cancer, Environmental Health, and Birth Defects
were supported from varying periods of time in Connecticut, western Washington State, the San Francisco,
California, Bay Area, metropolitan Atlanta, and metropolitan Houston, Texas.
Thereafter, ionizing radiation continued to be an
occasional topic for CDC field studies, especially in
the mid-1970s when concerns were raised about possible increased incidence of leukemia among military
personnel present during atmospheric nuclear weapon
tests in Nevada. The CDC conducted a study of personnel present at one such detonation (the "Smoky"
weapon test in 1957) and documented an increased
incidence of leukemia (22). Although no such increases have subsequently been seen in connection
with other nuclear tests (23), epidemiologic studies are
not yet complete. Soon after the Smoky investigation,
CDC personnel conducted studies of possible adverse
health effects in workers in the nuclear submarine and
nuclear weapons development industries (24, 25) and
in the population living near Three Mile Island (Pennsylvania).
Toxic substances
In addition to such radiation-related investigations,
the CDC in the 1970s participated increasingly in field
studies concerned with other kinds of environmental
exposures. Some of these studies were occupational in
nature, arising from collaborative work with epidemiologists from the National Institute for Occupational
Safety and Health: studies of 1) hepatic angiosarcoma
in vinyl chloride polymerization workers in plastic
industries (l), 2) neuromuscular disorders among pesticide production workers exposed to kepone in Virginia, and 3) neuromuscular disorders among workers
exposed to organic solvents at an Ohio coated-fabric
manufacturing plant.
More often than not, however, field studies involved
community exposures of various sorts that were
brought to the CDC's attention by state and local
health departments. Examples include 1) dioxin
(2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD» exposures at a Missouri horse arena where contaminated
waste oil was sprayed for dust control (26), 2) PBB
exposures in Michigan from contamination of dairy
products resulting from unintentional substitution of a
flame retardant chemical (PBB) for a cattle feed additive (3), 3) polychlorinated biphenyl exposures in
Indiana arising from contaminated sewage sludge used
for home gardening (27), 4) DDT exposure in a rural
Alabama town caused by consumption of fish contaminated by waste from a nearby wartime DDT production facility (5), and 5) lead exposures in Idaho and
Texas resulting from the airborne emissions of nearby
ore smelters (28). As the CDC's experience grew
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through work in such environmental epidemiology
studies, so did the diversity, and often the corrtplexity,
of the environmental issues for which CDC assistance
was requested. Exposure to toxic wastes at Love Canal
(New York) (29), to volcanic ash after the Mount St.
Helen's eruption (Washington State), and to summer
heat waves in the Midwest all called for CDC involvement. All such work led eventually to the more formal
responsibilities which the CDC and the Agency for
Toxic Substances and Disease Registry now hold for
studying widely different areas of potentially toxic
environmental exposures.
BIRTH DEFECTS AND DEVELOPMENTAL
DISABILITIES
MACDP
Birth defects are the leading cause of infant mortality and are responsible for substantial morbidity and
disability. Prevention is highly desirable but significantly constrained because the causes remain unknown for the vast majority of birth defects. The
MACDP was established to seek clues to etiology. As
a registry, it has provided timely case counts for surveillance, cases for case-control studies, and training
and growth opportunities for many individuals interested in doing birth defects surveillance and etiologic
research (30, 31).
Langmuir supported the MACDP, in part, because
there had been an epidemic of birth defects in Europe
from the drug thalidomide. Langmuir understood that
the systematic and timely collection and analysis of
birth defects incidence data could minimize the time
between the onset of an exposure in a population and
the discovery that the exposure was causing the disease. He understood, articulated, and expected that the
birth defects data would become a gold mine that
epidemiologists and other scientists would mine to
produce products that would improve the health of
children. At the 25th anniversary celebration of the
MACDP, Langmuir spoke with pride about the
achievements of this program that he had nurtured and
given broad direction to in its infancy. In this section
we review the MACDP's early years, highlight some
of its achievements, and examine the new directions
that have resulted from Langmuir's vision and support
for this area of public health.
The early MACDP
The MACDP was established by a first-year Epidemic Intelligence Service officer who was a pediatrician interested in birth defects and genetics and a
master's-level nurse working at the Georgia Mental
Health Institute. Hired in July 1967, they began col-
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Oakley and Heath
lecting data in October 1967 from all hospitals with an
obstetric or pediatric service in the five-county metropolitan Atlanta area, and from cytogenetic laboratories. They sent a monthly four-page summary of the
surveillance data back to those who had contributed
the data. In establishing the MACDP, they secured the
backing of the clinical community, the state epidemiologist, and the academic community in a matter of
weeks, which in retrospect was a remarkable feat.
It was not so much that the clinical community
valued the surveillance report as it was that it valued
access to an interested and qualified pediatric clinician
who would see some of the difficult diagnostic cases,
obtain chromosomal studies, and provide clinical interpretation to the physician and the family. This service was not only helpful to the community, but it also
helped bolster community support for the program and
improved the quality of the diagnosis of the cases in
the surveillance. As a part of the clinical workups,
histories were taken about the family and exposures in
pregnancy and provided data pertinent to discussions
with the family and became the foundation for casecontrol comparisons.
Thus, from its earliest days the MACDP was a
program seeking accurate and timely counts of cases
of birth defects in a defined population and clues to the
etiology of these cases. The surveillance data have
provided secular trend data, white and AfricanAmerican birth defects rates for comparisons in cluster
investigations, and for comparisons with other surveillance data. The learning experiences of the staff working on the MACDP provided the basis for informed
technical assistance to states and others seeking to
establish population-based surveillance of birth
defects.
Case-control studies
Once the surveillance system was well established,
attention shifted to the systematic collection of exposure data through interviews of the mothers of infants
with selected major birth defects. This case-control
surveillance provided the possibility for evaluating
associations between prenatal exposures-usually exposures to drugs-and birth defects. One important
outcome of the early interviews showed no association
between birth defects and Bendectin (Marion Merrell
Dow, Kansas City, Missouri)-an antinausea product
that about 20 percent of pregnant Atlanta women took
during their pregnancies (32).
Concern about the possible role of exposures to
chemicals used during the Vietnam War in causing
birth defects provided a major new opportunity to use
the MACDP to try to answer nationally important
etiologic questions about birth defects. The experi-
enced staff and the surveillance data on birth defects
from more than 300,000 births in metropolitan Atlanta
from 1968 through 1980 provided the CDC with the
ability to respond to this highly visible concern in a
timely fashion. New resources were provided, and a
large, sophisticated case-control study was conducted
which found no association between being a Vietnam
veteran and the occurrence of birth defects among
Veterans' offspring (33). That study, however, produced a valuable data source that continues to be
analyzed by the CDC (34).
Folic acid-preventable spina bifida and
anencephaly
In the late 1970s and early 1980s the question of
whether or not one or more vitamins would prevent
spina bifida was a topic of great interest. Scientists in
the birth defects group analyzed data from the Vietnam Veterans' case-control database and found a
strong protective effect between regular vitamin supplementation and spina bifida and anencephaly (35).
In the summer of 1991, the group became aware that
the British Medical Research Council's randomized
controlled trial showed that folic acid, a B vitamin,
could prevent spina bifida and anencephaly. The potential for improving human health from folic acid is
similar to the impact of improving human health from
the polio vaccines. The CDC birth defects group has
given great priority to trying to make this prevention a
reality (36), including taking the lead in producing, in
1991, recommendations for women who have had
spina bifida and anencephaly pregnancies and, in
1992, for women in the general population (37, 38).
Public health surveillance was used to point out the
continuing epidemic of severe birth defects that could
be prevented by increased consumption of folic acid
by fortification of cereal grain with sufficient folic
acid, by consuming folic acid containing vitamin supplements, and by consuming foods rich in folate (39).
In March 1996, the Food and Drug Administration
took an important step to increase consumption of
folic acid by issuing a regulation that will require all
"enriched" cereal-grain products to contain folic acid
at a concentration of 140 JLg of folic acid per 100 g of
grain. Through health education, the importance of
adequate folic acid intake for women of reproductive
age will be emphasized.
Chorionic villus sampling
Concern that a widely-used medical procedure, chorionic villus sampling, could cause birth defects recently prompted CDC staff to use not only cases in the
MACDP but also cases in five other birth defects
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Cancer, Environmental Health, and Birth Defects
registers to conduct an ad hoc multicenter case-control
study. This study showed that there was a small absolute risk for a certain kind of limb abnormality, and
these findings led to the publication of recommendations (40, 41). From a methodological point of view,
this study demonstrated that state-based birth defect
registries can play an important public health role by
promptly responding to public concern about possible
etiologic agents.
National birth defects monitoring
The MACDP was an important resource, but it was
not a national birth defects monitoring effort. Many
European countries had begun national birth defects
monitoring programs in response to the epidemic of
birth defects caused by thalidomide. The March of
Dimes Birth Defects Foundation prompted discussions
about establishing such a system using data from a
computer project that analyzed hospital data from hundreds of hospitals nationwide. In the early 1970s, the
CDC established the Birth Defects Monitoring Program, which was funded initially, in part, with money
from the National Institute of Child Health and Human
Development.
Although this data source is not population-based
and not a random sample of US births, it nevertheless
represents one of the largest single sources of uniformly collected and coded discharge data on birth
defects among newborns. This dataset has provided
trend data on up to 35 percent of the nation's births in
a timely fashion-within 6 months of the births. Furthermore, this dataset has provided the basis for the
year 2000 health objectives for lowering the prevalence of several birth defects (31). The number of
participating hospitals is rapidly decreasing, so the
CDC is actively exploring ways to build a national
surveillance program by working with our partners in
state and local health departments. More than 20 states
have birth defects surveillance activities.
International birth defects monitoring
In the early 1970s, the March of Dimes Birth Defects Foundation convened a working group to explore
establishing a forum for rapid, regular exchange of
birth defects surveillance and other epidemiologic
data. As a result, the International Clearinghouse for
Birth Defects Monitoring Systems was established,
and CDC staff have been actively involved. Through
the Clearinghouse and the associated Centre for Birth
Defects Studies, there has been a regular exchange of
data and collaborative studies for more than two decades (42). One visible result of this collaboration was
Am J Epidemiol
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S63
establishing valproic acid, an anticonvulsant, as a human teratogen (43).
THE FUTURE-GENETICS
Langmuir was fascinated by using epidemiology to
find the unknown cause for a group of sick people. He
discussed developing a teaching exercise that would
have used Mendel's experiments with peas to show
that genetics could be the "unknown" cause. Thus,
Langmuir understood that genetics played a substantial role in the cause of disease. The human genome
project will revolutionize our ability to understand the
host and the genetic causes of, and predispositions to,
disease of the host. Epidemiologic investigations will
be an integral part of understanding how genetic information predicts disease. Perhaps more important
will be the principles of studying populations to determine what the proper content of public health genetics will be. Although we cannot predict what public
health genetics will be like in the 21st century, we
think it likely that genetic epidemiologists at the CDC
will, following the Langmuirian example and principles, be leaders in conceptualizing and implementing
this rapidly growing and changing field of public
health genetics. A former Epidemic Intelligence Service officer, who came to the CDC after Langmuir, is
today a leader developing public health genetics in the
United States, building on the principles of epidemiology that Langmuir practiced and taught (44).
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