Dose Response

SOMATIC AND GENETIC DAMAGE FACTORS

The amount of somatic and genetic biologic damage a human being suffers as a result of radiation exposure depends on several factors. Ionizing radiation produces the greatest amount of biologic damage in the human body when a large dose of densely ionizing (high-LET) radiation is delivered to a large or radiosensitive area of the body.

SOMATIC EFFECTS

When living organisms (such as human beings) that have been exposed to radiation suffer biologic damage, the effects of this exposure are classified as somatic effects. Depending on the length of time from the moment of irradiation to the first appearance of symptoms of radiation damage, the effects are classified as either early or late somatic effects. If these effects are cell-killing and directly related to the dose received, they are termed nonstochastic (deterministic) somatic effects. Late effects of ionizing radiation that are mutational or randomly occurring biologic somatic changes, independent of dose, are termed stochastic (probabilistic) somatic effects.

Early non-stochastic (deterministic) somatic effects are those that appear within minutes, hours, days, or weeks of the time of radiation exposure. A substantial dose of ionizing radiation is required to produce biologic effects so soon after irradiation. The severity of these effects is dose-related. With the exception of certain lengthy high-dose-rate fluoroscopic procedures, diagnostic radiologic examinations do not usually impose radiation doses sufficient to cause early deterministic effects.

Dose-Response CurvesRadiobiologists engaged in research have a common goal to establish relationships between radiation and dose-response. The information obtained can be used to predict the risk of malignancy in human populations that have been exposed to low levels of ionizing radiation. The radiation dose-response relationship is demonstrated graphically through a curve that maps the observed effects of radiation exposure in relation to the dose of radiation received. As the dose escalates, so do most effects. In such a dose-response curve the variables, or numbers, are plotted along the axes of the graph to demonstrate the relationship between the dose received (horizontal axis) and the biologic effects observed (vertical axis). The curve is either linear (straight line) or nonlinear (curved to some degree) and depicts either a threshold dose or a nonthreshold dose.

1: a hypothetical linear (straight-line), nonthreshold curve of radiation dose-response relationship.

2: a hypothetical linear (straight-line), threshold curve of radiation dose-response relationship

3: a hypothetical nonlinear, threshold curve of radiation dose-response relationship

Threshold may be defined as a point at which a response or reaction to an increasing stimulation first occurs. With reference to ionizing radiation, this means that below a certain radiation level or dose, no biologic effects are observed. Biologic effects are observed only when the threshold level or dose is reached. A nonthreshold relationship means that any radiation dose will produce a biologic effect. No radiation dose is believed to be absolutely “safe.” Therefore, if ionizing radiation functions as the stimulus and the biologic effect it produces is the response, and if a nonthreshold relationship exists between radiation dose and a biologic response some biologic effects will be caused in living organisms by even the smallest dose of ionizing radiation.

treshold

Risk Models Used to Predict Cancer Risk and Genetic Damage in Human Populations

In a 1980 report the Committee on the Biological Effects of Ionizing Radiation (BEIR), under the auspices of the National Academy of Sciences, revealed that the majority of stochastic somatic effects (e.g., cancer) and genetic effects at low-dose levels from low-LET radiations, such as those employed in diagnostic radiology, appear to follow a linear-quadratic nonthreshold curve. New risk models and updated dosimetry techniques have provided a better follow-up study of Hiroshima and Nagasaki atomic bomb survivors. In 1990 the BEIR Committee's revised risk estimates indicated that the risk of radiation exposure was about three to four times greater than previously projected. Currently the committee recommends the use of the linear, nonthreshold curve of radiation dose-response for most types of cancer. The linear, nonthreshold curve implies that the biologic response to ionizing radiation is directly proportional to the dose.

The linear-quadratic, nonthreshold curve estimates the risk associated with low-level radiation. As previously stated, the BEIR Committee believes it is a more accurate reflection of stochastic somatic and genetic effects at low-dose levels from low-LET radiations. Leukemia, breast cancer, and heritable damage are presumed to follow this curve. For leukemia, the linear-quadratic, non-threshold curve is supported by an analysis of the leukemia occurrences in Nagasaki and Hiroshima using a recent reevaluation of the radiation dose distribution in these two cities.

The linear-quadratic model includes extra mathematical terms that produce a deviation from straight-line behavior at low doses so that the risk per additional centigray (rad) at low doses is predicted to be less than at high doses. The 1989 BEIR V report supported the linear-quadratic model for leukemia only. For all other cancers the BEIR V Committee recommended adoption of the linear model to fit the available data.

The continued use of the linear dose-response model for radiation protection standards has the potential to exaggerate the seriousness of radiation effects at lower-dose levels from low-LET radiations. However, it accurately reflects the effects of high-LET radiations (neutrons and alpha rays) at higher doses. In establishing radiation protection standards, the regulatory agencies have chosen to be conservative—that is, to use a model that might overestimate risk but is not expected to underestimate risk.

This model predicts that the number of excess cancers will increase as the natural incidence of cancer increases with advancing age in a population.

The BEIR Committee has further stated that because of the uncertainty in its analysis, less than 1 rad/yr may not be harmful.

BEIR Committee Estimated Excess Mortality From Malignant Disease in 100,000 People

Cause Your Chance of Dying This Year

All causes (all ages) 1 in 100

20 cigarettes per day 1 in 280

Heart disease 1 in 300

Cancer 1 in 520

All causes (25-year-old) 1 in 700

Stroke 1 in 1200

Motor vehicle accident 1 in 4000

Drowning 1 in 30,000

Alcohol (light drinker) 1 in 50,000

Air travel 1 in 100,000

Radiation, 100 mrad 1 in 100,000

Texas Gulf Coast hurricane 1 in 4,500,000

Being a rodeo cowboy 1 in 6,200,000

Risk Model Used to Predict High-Dose Cellular Response

Nonstochastic effects of significant radiation exposure such as skin erythema and hematologic depression may be demonstrated graphically through the use of a linear, threshold curve of radiation dose-response. Here, a biologic response does not occur below a specific dose level. Laboratory experiments on animals and data from human populations observed after acute high doses of radiation provided the foundation for this curve.

The sigmoid or “S-shaped” (nonlinear), threshold curve of radiation dose–response relationship is generally employed in radiation therapy to demonstrate high-dose cellular response. This curve indicates the existence of a threshold, a minimal dose of ionizing radiation below which observable effects will not occur. Different effects require different minimal doses. The tail of the curve indicates that limited recovery occurs at low radiation doses. At the highest radiation doses, the curve gradually levels off and then veers downward because the affected living specimen or tissue dies before the observable effect appears.

Somatic and Genetic Damage Factors:

• The quantity of ionizing radiation to which the subject is exposed

• The ability of the ionizing radiation to cause ionization of human tissue

• The amount of body area exposed• The specific body parts exposed

High-dose effects include:

• nausea, fatigue• erythema (diffuse redness over an area of skin after irradiation) • epilation (loss of hair)• blood disorders• intestinal disorders• fever• dry and moist desquamation (shedding of the outer layer of skin) • depressed sperm count in the male• temporary or permanent sterility in the male and female, • injury to the central nervous system (at extremely high radiation

doses).

Erythema - radiodermatitis

Desquamation

These early somatic effects are called acute radiation syndrome (ARS).

Low-dose, chronic irradiation does not impair fertility.

The health effects analysis of 150,000 American radiologic technologists has revealed no effect on fertility. The number of births that occurred during a 12-year sampling period equaled the number expected.

Animal data in this area are lacking. Those that are available indicate that, even when radiation is delivered at the rate of 100 rad per year, no noticeable depression in fertility is noted

Irradiation in utero

Irradiation in utero concerns the following two types of exposures:

• that of the radiation worker• that of the patient

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.

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.

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.

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.

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. Although these findings have been substantiated in several American populations, no consensus has been reached among radiobiologists that this effect after such low doses is indeed real.

Time of X-Ray Examination Relative Risk

First trimester 8.3

Second trimester 1.5

Third trimester 1.4

Total 1.5

Relative Risk of Childhood Leukemia After Irradiation In Utero by Trimester

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 mental retardation.

Time of Exposure Type of Response Natural Occurrence Radiation Response

0-2 wk Spontaneous abortion 25% 0.1%

2-10 wkCongenital abnormalities

5% 1%

2-15 wk Mental retardation 6% 0.5%

0-9 mo Malignant disease 8/10,000 12/10,000

0-9 moImpaired growth and development

1% Nil

0-9 mo Genetic mutation 10% Nil

Summary of Effects After 10 Rad In Utero