Radiation Long Term Effects II

Substantial animal data are available to describe fairly completely the effects of relatively high doses of radiation delivered during various periods of gestation. Because the embryo is a rapidly developing cell system, it is particularly sensitive to radiation. With age, the embryo (and then the fetus) becomes less sensitive to the effects of radiation, and this pattern continues into adulthood. After maturity has been reached, radiosensitivity increases with age

All observations point to the first trimester during pregnancy as the most radiosensitive period.

The effects of radiation in utero are time related and dose related The effects of radiation in utero are time related and dose related. They include prenatal death, neonatal death, congenital abnormalities, malignancy induction, general impairment of growth, genetic effects, and mental retardation. The preceeding figure has been redrawn from studies designed to observe the effects of a 200-rad (2-Gyt) dose delivered at various stages in utero in mice. The scale along the x-axis indicates the approximate comparable time in humans. Within 2 weeks of fertilization, the most pronounced effect of a high radiation dose is prenatal death, which manifests as a spontaneous abortion. Observations in radiation therapy patients have confirmed this effect, but only after very high doses. On the basis of animal experimentation, it would appear that this response is very rare. Our best estimate is that a 10-rad (100-mGyt) dose during the first 2 weeks will induce perhaps a 0.1% rate of spontaneous abortion. This occurs in addition to the 25% to 50% normal incidence of spontaneous abortions. Fortunately, this response is of the all-or-none variety: Either a radiation-induced abortion occurs, or the pregnancy is carried to term with no ill effect.

The first 2 weeks of pregnancy may be of least concern because the response is all-or-nothing.

During the period of major organogenesis, from the 2nd through the 10th week, two effects may occur. Early in this period, skeletal and organ abnormalities can be induced. As major organogenesis continues, congenital abnormalities of the central nervous system may be observed if the pregnancy is carried to term.

If radiation-induced congenital abnormalities are severe enough, the result will be neonatal death. After a dose of 200 rad (2 Gyt) to the mouse, nearly 100% of fetuses suffered significant abnormalities. In 80%, this was sufficient to cause neonatal death.

Irradiation in utero at the human level has been associated with childhood malignancy by a number of investigators. The most complete study of this effect was conducted by Alice Stewart and coworkers in a project known as the Oxford Survey, a study of childhood malignancy in England, Scotland, and Wales. Nearly every such case of childhood malignancy in these countries since 1946 has been investigated. Each case was first identified and then investigated by interview with the mother, review of the hospital charts, and review of the physician records. Each “case” of childhood malignancy was matched with a “control” for age, sex, place of birth, socioeconomic status, and other demographic factors. The control subject was a child who matched with the “case” in all respects, except that the control did not have cancer or leukemia. The Oxford Survey is being continued at this time and has now considered more than 10,000 cases and a like number of matched control subjects

The relative risk of childhood leukemia after irradiation in utero is 1.5 A relative risk of 1.5 for the development of childhood leukemia after irradiation in utero is significant. This indicates an increase of 50% over the nonirradiated rate. The number of cases involved, however, is small

Other effects after irradiation in utero have been studied rather fully in animals and have been observed in some human populations. An unexpected finding in the offspring of atomic bomb survivors is mental retardation. Children of exposed mothers performed poorly on IQ tests and demonstrated poor scholastic performance compared with unexposed Japanese children.

Radiation exposure in utero does retard the growth and development of the newborn. Irradiation in utero, principally during the period of major organogenesis, has been associated with microcephaly (small head) and, as discussed, mental retardation.

The incidence of childhood leukemia in the population at large is approximately 9 cases per 100,000 live births. According to the Oxford Survey, if all 100,000 had been irradiated in utero, perhaps 14 cases of leukemia would have resulted

Human data bearing on these effects have been obtained from patients irradiated medically, atomic bomb survivors, and residents of the Marshall Islands who were exposed to radioactive fallout in 1954 during weapons testing. For instance, heavily irradiated children at Hiroshima are, on average, 2.25 cm (0.9 in) shorter, 3 kg (6.6 lb) lighter, and 1.1 cm (0.4 in) smaller in head circumference than members of nonirradiated control groups. These effects, as well as mental retardation, have been observed principally in those receiving doses in excess of 100 rad (1 Gyt) in utero. The lack of appropriate and sensitive tests of mental function makes it impossible to draw similar conclusions at doses below 100 rad (1 Gyt).

Relative Risk of Childhood Leukemia After Irradiation In Utero by Trimester Time of X-Ray Examination Relative Risk First trimester 8.3 Second trimester 1.5 Third trimester 1.4 Total

Summary of Effects After 10 Rad In Utero Time of Exposure Type of Response Natural Occurrence Radiation Response 0-2 wk Spontaneous abortion 25% 0.1% 2-10 wk Congenital abnormalities 5% 1% 2-15 wk Mental retardation 6% 0.5% 0-9 mo Malignant disease 8/10,000 12/10,000 Impaired growth and development Nil Genetic mutation 10%

Four responses of concern to radiology have been identified: spontaneous abortion, congenital abnormalities, mental retardation, and childhood malignancy.

Spontaneous abortion causes the least concern of the four because it is an all-or-none effect. Congenital abnormalities, mental retardation, and childhood malignancy are of real concern, but it should be recognized that the probability of such a response after a fetal dose of 10 rad (100 mGyt) is nil. Furthermore, 10 rad (100 mGyt) to the fetus very rarely occurs in radiology. No evidence in humans or animals indicates that the levels of radiation exposure currently experienced occupationally and medically are responsible for any such effects on growth and development

Genetic Effects Unfortunately, our weakest area of knowledge in radiation biology is the area of radiation genetics. Essentially all the data indicating that radiation causes genetic effects have come from large-scale experiments with flies or mice

In 1927, the Nobel prize–winning geneticist H. J In 1927, the Nobel prize–winning geneticist H.J. Muller from the University of Texas reported the results of his irradiation of Drosophila, the fruit fly. He irradiated mature flies before procreation and then measured the frequency of lethal mutations among the offspring. The radiation doses used were thousands of rad, the dose-response relationship for radiation-induced genetic damage is linear, nonthreshold. On the basis of Muller's studies, other conclusions were drawn. Radiation does not alter the quality of mutations but rather increases the frequency of those mutations that are observed spontaneously. Muller's data showed no dose rate or dose fractionation effects. Hence, he concluded that such mutations were single-hit phenomena.

Irradiation of flies by H. J Irradiation of flies by H.J. Muller showed the genetic effects to be linear, nonthreshold. Note that the doses were exceedingly high.

It was principally on the basis of Muller's work that the National Council on Radiation Protection in 1932 lowered the recommended dose limit and acknowledged officially for the first time the existence of nonthreshold radiation effects. Since then, all radiation protection guides have assumed a linear, nonthreshold dose-response relationship and have been based on the suspected genetic, as well as somatic, effects of radiation.

The only other experimental work of any significance is that of Russell. Beginning in 1946, he began to irradiate a large mouse colony with radiation dose rates that varied from 0.001 to 90 rad/min (0.01 to 900 mGyt/min) and total doses up to 1000 rad (10 Gyt). These studies are ongoing, and observations now have been reported on more than 8 million mice! The experiment requires the observation of seven specific genes that control readily recognizable characteristics, such as ear shape, coat color, and eye color. Russell's data show that a dose rate effect does exist; this would indicate that the mouse has the capacity to repair genetic damage. He has confirmed the linear, nonthreshold form of the dose-response relationship and has not detected any types of mutations that did not occur naturally. The average mutation rate per unit dose in the mouse is approximately 15 times that observed in the fruit fly. Whether an increased sensitivity exists in humans relative to the mouse is unknown.

We do not have any data that suggest that radiation-induced genetic effects occur in humans Observations of the atomic bomb survivors have shown no radiation-induced genetic effects, and descendants of survivors are now into the third generation. Other human populations have likewise provided only negative results. Consequently, in the absence of accurate human data, there is no choice but to rely on information from experimental laboratory studies.

The doubling dose is that dose of radiation that produces twice the frequency of genetic mutations as would have been observed without the radiation The doubling dose in humans is estimated to lie in the range between 50 and 250 rad (0.5 and 2.5 Gyt).

• Radiation-induced mutations are usually harmful. • Any dose of radiation, however small, to a germ cell results in some genetic risk. • The frequency of radiation-induced mutations is directly proportional to dose, so that a linear extrapolation of data obtained at high doses provides a valid estimate of low-dose effects. • The effect depends on radiation protraction and fractionation. • For most pre-reproductive life, the woman is less sensitive than the man to the genetic effects of radiation. • Most radiation-induced mutations are recessive. These require that the mutant genes must be present in both the male and the female to produce the trait. Consequently, such mutations may not be expressed for many generations. • The frequency of radiation-induced genetic mutations is extremely low. It is approximately 10−7 mutations/rad/gene.

The incidence of radiation-induced genetic mutations after the levels of exposure experienced in diagnostic radiology is essentially zero