Critical windows of exposure for children’s health and agents related to childhood cancer

The carcinogenic effects of both ionizing radiation and DES may be mediated via teratogenesis

Abstract

In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal.

Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive.

Critical windows of exposure for children’s health: cancer in human epidemiological studies and neoplasms in experimental animal models, Environ Health Perspectives, NCBI PubMed PMID: 10852857, 2000 Jun.

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In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.

DIETHYLSTILBESTROL EXPOSURE

Unlike the situation for preconceptional exposures, there is good evidence that exposure of the human fetus to certain potentially harmful agents can increase the risk of cancer during childhood and possibly during early adulthood. Nonetheless, although numerous potentially harmful agents are suspected including infections, drugs, and maternal lifestyle characteristics the only two generally accepted carcinogenic in utero exposures are ionizing radiation and DES: the former acting directly on the fetus and the latter acting via the placenta.

The strong associations for DES have led researchers to postulate in utero effects for other endogenous and exogenous hormones, particularly for cancers with a suspected hormonal component to their etiology such as breast and testicular cancers. Further, since the birth of the first test-tube baby in 1978 there has been concern about the health of offspring resulting from assisted reproductive technology (ART). Multiple pregnancies often result from ART, which is one of the main determinants of the health of the child at birth. The importance of follow-up studies of these children to assess adverse health outcomes diagnosed after birth, even in adulthood, has been recognized, but few comprehensive and powerful epidemiological studies have been done. Two case reports have highlighted possible increases in cancer incidence in children born as a result of in vitro fertilization, raising concerns about the role of prenatal exposure (before and after conception) to high levels of estrogen and related compounds used for ovarian stimulation. To date, there are limited epidemiological data on this topic; a study of U.K. births after ART failed to find an excess incidence of childhood cancer, but, as noted by the authors, the study was too small to be able to detect a reasonable excess, even if it existed.

With respect to mechanisms and the timing of exposure, it is thought that the carcinogenic effects of both ionizing radiation and DES may be mediated via teratogenesis. This has been documented for DES, which causes various genital tract abnormalities in males as well as in females. In addition, it has been suggested that the exposure of pregnant women to substances that inhibit the function of the topoisomerase II enzymes could be related to the development of acute leukemia in their offspring.

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Diethylstilbestrol Exposure and Leukemia, Brain Tumors, Wilms’ tumor

Childhood cancer: overview of incidence trends and environmental carcinogens

Abstract

An estimated 8000 children 0 to 14 years of age are diagnosed annually with cancer in the United States. Leukemia and brain tumors are the most common childhood malignancies, accounting for 30 and 20% of newly diagnosed cases, respectively.

From 1975 to 1978 to 1987 to 1990, cancer among white children increased slightly from 12.8 to 14.1/100,000. Increases are suggested for leukemia, gliomas, and, to a much lesser extent, Wilms’ tumor.

There are a few well-established environmental causes of childhood cancer such as radiation, chemotherapeutic agents, and diethylstilbestrol.

Childhood cancer: overview of incidence trends and environmental carcinogens, Environ Health Perspectives, NCBI PubMed PMID: 8549470, 1995 Sep.

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Many other agents such as electromagnetic fields, pesticides, and some parental occupational exposures are suspected of playing roles, but the evidence is not conclusive at this time.

Some childhood exposures such as secondhand cigarette smoke may contribute to cancers that develop many years after childhood.

For some exposures such as radiation and pesticides data suggest that children may be more susceptible to the carcinogenic effects than similarly exposed adults.

Diethylstilbestrol exposure and Medications

Transplacental carcinogenesis was established by the discovery in 1971 of vaginal adenocarcinoma in the daughters of women who took the hormone diethylstilbestrol (DES) during pregnancy to avoid miscarriages. This very rare cancer has been detected in girls as young as 7 years old, with most affected between 15 and 22 years of age. There are concerns that at older ages the exposed daughters may also have increased risk of squamous carcinomas of the vagina and cervix and cancers of the breast and that exposed sons may have excess testicular and prostate cancer . Continued followup of the DES-exposed daughters and sons is ongoing at the National Cancer Institute and may provide further information on the late effects of DES and on transplacental carcinogenesis in general.

Suspected, but less well-established, of being a transplacental carcinogen is phenytoin, an antiepileptic drug. There are reports of neuroblastoma and soft tissue sarcoma in children exposed in utero to phenytoin.

There have also been reports of excess brain tumors, neuroblastomas, leukemia, and retinoblastomas in children of women who used antinausea medications (e.g., Bendectin) during pregnancy. This issue had received considerable publicity, however, which may have affected recall of use by study subjects. One study used medical records, not subject recall, to assess exposure and did not show any associations.

There is one report of excess Wilms’ tumor among Swedish children whose mothers were exposed to penthrane (methoxyflurane) anesthesia during delivery. The excess risk was higher in females and increased with age at diagnosis.

Some medical treatments received during childhood also play a role in the development of childhood cancer. Chemotherapy and radiation therapy received for an initial childhood cancer can dramatically increase the risk for second cancers. For example, in one study children treated with alkylating agents for cancer have a 5-fold risk of subsequently developing leukemia. At high doses, the risk was increased as much as 25 times the expected rate of leukemia. Bone sarcomas were also elevated in children treated with radiation and chemotherapy.

The potent antibiotic chloramphenicol, given to treat life-threatening infectious conditions, has been linked to excess acute lymphocytic leukemia and acute nonlymphocytic leukemia in children in Shanghai. This association with leukemia is consistent with a report of bone marrow depression following use of chloramphenicol.

Parental use of illegal drugs has been linked to childhood cancer in a few reports. Marijuana use was associated with rhabdomyosarcoma, leukemia, and brain tumors. Cocaine use was also associated with rhabdomyosarcoma.

These exposures are difficult to study accurately and need further research, but prevention efforts clearly must continue for noncancer-related reasons even in the absence of convincing data on childhood cancer.

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Chest radiation to treat Wilms tumor childhood cancer increases risk of breast cancer later in life

Breast cancer in female survivors of Wilms tumor:
a report from the National Wilms Tumor late effects study

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Breast cancer in female survivors of Wilms tumor: a report from the National Wilms Tumor late effects study

A new study has found that patients who received chest radiation for Wilms tumor, a rare childhood cancer, face an increased risk of developing breast cancer later in life due to their radiation exposure. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings suggest that cancer screening guidelines might be re-evaluated to facilitate the early diagnosis and prompt treatment of breast cancer among Wilms tumor survivors.

Wilms tumor is a rare childhood kidney cancer that can spread to the lungs. When this spread occurs, patients receive a relatively low dose of 12-14 Gray of radiation therapy to the entire chest. To see if such exposure to radiation affects patients’ risk of developing breast cancer, Norman Breslow, PhD, of the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, led a team that studied nearly 2500 young women who had been treated for Wilms tumor during childhood and who had survived until at least 15 years of age.

Of female Wilms tumor survivors who received radiation to the chest, over 20% developed breast cancer by age 40 years (3/4 invasive, 1/4 non-invasive), in contrast to only 0.3% in female Wilms tumor survivors who did not receive radiation. The researchers also found an intermediate risk (4%) of breast cancer among female Wilms tumor patients who had received abdominal but no chest radiation as part of their treatment for Wilms tumor. The rates for females receiving chest irradiation, abdominal radiation and no radiation are nearly 30, 6, and 2 times those expected among women of comparable age in the general population. This high incidence of breast cancer, including invasive cancer, was an unexpected finding.

Current guidelines call for early screening for breast cancer among survivors of childhood cancer if they have received 20 or more Gray of radiation therapy to breast tissue. This would exclude a large majority of patients who had received whole chest radiation for Wilms tumor,” said Dr. Breslow. “Our results suggest that the risk of early breast cancer among Wilms tumor survivors is sufficiently high that early screening might be considered an option for them also.”

In an accompanying editorial, Jennifer Dean, MD and Jeffrey Dome, MD, PhD of Children’s National Health System in Washington, DC, noted that Wilms tumor survivors at high risk should undergo breast cancer surveillance with mammogram, breast MRI, or both starting at age 25 years. However, they pointed to research indicating that less than half of childhood cancer survivors considered to have a high risk for breast cancer follow through with surveillance guidelines. “Because compliance with breast cancer surveillance is low in adult survivors of childhood cancer, barriers such as education of both survivors and providers should be addressed and mitigated,” they wrote.

Sources and more information:

  • Chest Radiation to Treat Childhood Cancer Increases Patients’ Risk of Developing Breast Cancer,
    WileyCDA Press Release, October 27, 2014.
  • Breast cancer in female survivors of Wilms tumor: A report from the National Wilms Tumor late effects study,
    Wiley Online Library, DOI: 10.1002/cncr.28908, 27 OCT 2014.