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Stilbestrol

Diethylstilbestrol (DES) is a drug, a synthetic estrogen that was developed to supplement a woman's natural estrogen production. First prescribed by physicians in 1938 for women who experienced miscarriages or premature deliveries, DES was originally considered effective and safe for both the pregnant woman and the developing baby. A double-blind study was not done until DES had been on the market for more than a decade (Dieckmann, 1953). Even though it found that pregnant women given DES had just as many miscarriages and premature deliveries as the control group, DES continued to be aggressively marketed and routinely prescribed. more...

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In the United States, an estimated 5-10 million persons were exposed to DES during 1938-1971, including women who were prescribed DES while pregnant and the female and male children born of these pregnancies. In 1971, the Food and Drug Administration (FDA) issued a Drug Bulletin advising physicians to stop prescribing DES to pregnant women because it was linked to a rare vaginal cancer in female offspring.

More than 30 years of research have confirmed that health risks are associated with DES exposure. However, not all exposed persons will experience the following DES-related health problems.

Women prescribed DES while pregnant are at a modestly increased risk for breast cancer.

Women exposed to DES before birth (in the womb), known as DES Daughters, are at an increased risk for clear cell adenocarcinoma (CCA) of the vagina and cervix, reproductive tract structural differences, pregnancy complications, and infertility. Although DES Daughters appear to be at highest risk for clear cell cancer in their teens and early 20s, cases have been reported in DES Daughters in their 30s and 40s (Hatch, 1998).

Men exposed to DES before birth (in the womb), known as DES Sons, are at an increased risk for non-cancerous epididymal cysts.

Researchers are still following the health of persons exposed to DES to determine whether other health problems occur as they grow older.

Current research also looks at DES Third Generation. Third Generation refers to the offspring of DES Sons and Daughters. There is not yet much information available because the Third Generation are at an age where they can start to be physiologically affected by the DES exposure of his or her parent(s).

Third generation injuries are associated with preterm labor or deliveries resulting in premature birth and cerebral palsy, blindess or other neurological deficits or death of a child. One DES Daughter had a child who, at the age of four years, had such a severe case of cerebral palsy that the child was unable to turn himself over; the cerebral palsy was linked to the DES exposure of the mother.

Another study (J Pediatr Hematol Oncol 2003; 25:635-636.) found DES to be transgenerational, meaning that the maternal grandmother had taken DES while pregnant but the mother did not experience any health associated with the DES exposure. This was realized when a rare tumor was discovered on a 15 year old girl.

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A cluster of childhood leukemia near a nuclear reactor in Northern Germany
From Archives of Environmental Health, 7/1/97 by Wolfgang Hoffmann

"CLUSTER" ANALYSIS has become a widely used term for the study of spatial disease patterns in small geographical areas.[1] Although ecological by definition, many small area studies have been supplemented with investigations at the individual level. Cluster analysis then extends beyond the ecological perspective, and Rose[2] has referred to it as "microepidemiology." Although some researchers have criticized microepidemiology for its conceptual and methodological limitations,[3,4] some well-known examples nevertheless prove its principal potential as a useful tool in environmental epidemiology.[5-9]

Results of cluster analysis and microepidemiology have become key arguments in a debate on leukemia risks for children who live in the vicinity of nuclear facilities. Researchers have reported increased risks in geographical studies in England and Wales, Scotland, the United States,[10-14] Canada,[15] Germany,[16-21] and more recently in France.[22,23]

Descriptive Epidemiology

The rural community of Elbmarsch includes several small villages located at the southern bank of the Elbe River, 35 km southeast of Hamburg in northern Germany. Between February 1990 and May 1991, professionals diagnosed five cases of leukemia in children under age 15 y in the rural community of Elbmarsch. We excluded another leukemia case (i.e., 21-y-old male) from the analysis. In early summer 1995, professionals diagnosed another 10-y-old child with acute leukemia in one of the villages, thus increasing the total number of childhood leukemia cases to six (Table 1). Fortunately, leukemia occurs rarely in childhood. In Germany, the age-adjusted incidence for all types of leukemia combined in children below age 15 y is 4.3/100 000 person-years (data for 1989-1993[24]). The leukemias account for approximately 30% of all malignancies that occur before age 15y.[24]

Table 1. -- Childhood and Juvenile Leukemia Cases in the Rural Community Elbmarsch, Northern Germany

2. With respect to a given dose of radiation, the relative risk for leukemia increases with younger age by a factor of 4-5 (adults versus children below the age of 5 y[72]). For prenatal exposure, we can derive a factor of approximately 70 from data of the Oxford Survey of Childhood Cancers (OSCC).[67,73]

3. Preconceptional exposure[36-42] may add a potential exposure pathway that cannot yet be accounted for in risk coefficients. Incorporated radionuclides may be of particular concern, but the magnitude of this potential effect is unknown presently.[40]

4. Effects of complex combinations of environmental exposures are still very poorly understood. Nevertheless, synergistic effects between irradiation and chemical exposures could well enhance the leukemogenic potential of either factor.[74,75]

Most important, exposure assessment in such studies is usually inadequate. Routine environmental radiation surveillance can fail to detect chronic exposures from short-lived [Beta]-emitters or from extremely inhomogeneous spatial/temporal distributions of radionuclides. Indeed, we speculated earlier that elevated rates of structural chromosomal aberrations in a casual sample of five parents of leukemia cases and four other adult Elbmarsch residents would be compatible with past releases of short-lived fission products, which might have been missed by routine surveillance (2.4 dicentric chromosomes/1 000 metaphases observed, 0.4/1 000 expected; p [is less than] .0001).[76]

The recent results of high-geographical-resolution incidence mapping also revealed a significantly elevated leukemia incidence for adults in the 5-km-radius region around the plant during the years 1984-1993 (all leukemias: 41 cases observed, 30 expected; SIR = 128; p [is less than] .05).[77]

At this time, microepidemiology cannot provide any further insight. Individual exposure to releases from the plant as well as to known or other suspected other risk factors for childhood and adult leukemia need to be investigated quantitatively. Exposure assessment will be crucial in a large case-control study that has been commissioned recently by the Ministry for the Environment, Natural Protection and Forests of Schleswig-Holstine and the Ministry of Social Affairs of Lower Saxony.

Since submission of this manuscript, three additional childhood leukemia cases (all males) were ascertained in the 0-5-km region around the nuclear power plant Kruemmel. Two of the cases were diagnosed with acute lymphatic leukemia in 1995 and 1996, respectively. The third child had been diagnosed with acute myeloid leukemia already in 1994, but became known to us only very recently. These additional cases bring the total childhood leukemia cases in the immediate vicinity of the plant to nine. The appearance of new cases strongly indicates that childhood leukemia incidence remains elevated in the 0-5-km region around the plant. We cannot presently exclude the possibility that any underlying causal process might be ongoing.

Submitted for publication March 22, 1996; revised; accepted for publication August 26, 1996.

Requests for reprints should be sent to Wolfgang Hoffmann, Bremen Institute for Prevention Research and Social Medicine, Grunen-str. 120, D-28211 Bremen, Germany.

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