2. 2.3 Biological (Tissue, Organ and Systemic) Effects of Ionizing Radiation Hanaa A. Hassan

3. Development of Radiation Injury IONIZATION & EXCITATION CHEMICAL CHANGE (free radical formation) BIOLOGIC CHANGE (DNA damage ) MALIGNANT TRANSFORMATION OF CELLS CANCER MUTATIONS GENETIC EFFECTS INHIBITION of CELL DIVISION (cell death) ACUTE SOMATIC AND TERATOGENIC EFFECTS Gamma and x-rays Ionizing Particles (alpha, beta, protons, etc.)

4. THE EFFECTS OF RADIATION ON BIOLOGICAL SYSTEMS: TISSUES Highly sensitive to radiation killing are the cells of the hematopoietic system and related lymphoid system. Most sensitive are the stem cells of the bone marrow, which give rise to all circulating blood cells and platelets, as well as the lymphoid tissues found in the spleen, liver, lymph nodes and thymus. Hematopoietic System

5. Circulating lymphocytes are quite sensitive to radiation and a measurable drop in the normal titre (about 21,000/dl) can meter radiation exposure and indicate dose levels. As little as 10 cGy can show a measurable drop in the circulating small lymphocyte population. Of particular resistance are the mature circulating red blood cells and platelets; this is probably due to their lack of a nucleus.

6. Hematopoietic System Within the blood-forming organs are precursor cells that are killed by radiation. The subsequent effect on circulating cell levels is not seen for days to weeks because resistant mature cells in circulation remain viable. Only after these begin to diminish by natural turnover does the decrease in cell levels become evident, because the damaged bone marrow has made no replacements.

7. Hematopoietic System The effect is pan-cytopenia (depression of all cell types), resulting in hemorrhage (platelet reduction), infection (white-cell depression), and the effect of anemia from plummeting red cells.

8. Reproductive System The cells of the reproductive system are highly sensitive to radiation effects In the human male, stem cells and proliferating spermatogonia are highly sensitive. However, spermatids and mature sperm show considerable resistance. Also resistant are the interstitial cells of the testis, which control hormone production and secondary sexual characteristics. Therefore at sterilizing doses of 6 Gy, potency, fluid production of the prostate and seminal vesicles, as well as voice, beard and male social behavior are not affected.

9. Reproductive System With a turnover time for spermatogenesis (stem cell to mature sperm) of 64 to 72 days, sterility is never seen immediately after the radiation dose, because mature sperm are resistant to the killing effects of radiation. They can sustain heritable genetic damage, however. Doses of about 6 Gy are required to permanently sterilize males (sterility occurs after several months). Although lower doses can also cause sterility after several months, the effect is temporary. Fertility and near-normal sperm counts return after 1 to 2 years.

10. Reproductive System Dose rate has an unusual effect on the incidence of sterility in males. In animals it was found that dose protraction and fractionation were more effective in causing permanent sterility. This may be a result of synchronizing the sperm stem cells. Proliferating stem cells in the G 2 phase or M phase of the cell cycle are killed by radiation. But since the dose is protracted at a constant low rate, resistant S and G 1 cells eventually progress to the sensitive phases and are killed.

11. Reproductive System-Female Rradiation destroys both ovum and maturing follicules. This reduces hormon production. Therefore radiogenic sterility in females can be accompanied by artificial menopause, with significant effects on sexual characteristics and secondary genitalia.

12. Reproductive System-Female Total dose, dose rate, and age are important factors in the final effect. Younger women seems better able to recover fertility than do older women. A dose of 2 Gy permanently sterilizes women over 40 but causes temporary sterility in women age 35 and under. Menopouse was caused in 50% of younger women exposed to doses of 1,5 to 5 Gy. Women over 40 showed 90% menapouse at 1,5 Gy.

13. Gastrointestinal System The gastrointestinal (GI) tract is highly sensitive to radiation. Following irradiation, the first changes seen occur in the epithelium lining of the small intestine containing millions of convolutions called villi. The crypt cells of the villi are highly proliferative, supplying cells that continue to differentiate and migrate to the terminal villus. There they eventually slough off into the intestinal contents. Radiation causes mitotic arrest of the crypt cells followed by eventual denudation of the villi, ulceration of the wall, and septic infiltration.

14. Gastrointestinal System Effects on the large intestine cause functional impairment resulting in fluid and electrolyte loss, and diarrhea. Effects on the upper GI tract include vomiting, depression of acid, and pepsin secretion. Destruction of the epithelium lining of the phrynx and esophagus results in dryness, soreness, and petechia (capillary rupture).

15. Skin Skin is relatively radiosensitive. The radiobiologic end-points in skin are dependent on the total dose, the dose rate, and the radiation quality. Radiobiologic effects in skin include erythema (skin reddening), and temporary epilation (hair loss). At very high doses, permanent epilation and destruction of suborgans, including the vasculature, sebaceous and sweat gland, occur.

16. Skin The response of the skin to ionizing radiation is called radiation dermatitis. This effect follows a temporal as well as dose response depending on damage to the suborgans and connective tissue. Skin responses include: 1. Initial erythema. Redness occurs within days due to capllary dilatation caused by histamine releases. Threshold dose is 2 Gy from beta radiation or 1000 R from x-ray radiation.

17. Skin 2. Dry desquamation. After several days the epidermis scales and peels as a result of reduction in sebaceous and sweat gland secretion, and vascular damage. 3. Erythema proper. After the third or fourth week redness with soreness and burning and edema results. This is caused by obstructive changes in the fine vasculature in the dermis. 4. Moist desquamation. At high doses of 2000 R, blisters form in the epidermis, permanent epilation results and edema with macrophage infiltration occurs. Severe damage to the vasculature and connective tissue is the cause.

18. Skin 5. Necrosis. At very high doses, dermal necrosis may result after erythema proper as a result of dermis destruction, or later because of obstructive changes in arterioles, infection, and subcutaneous- fat-cell destruction. 6. Late effects. After one year, at high doses dermal atrophy, deep fibrosis, hyperpigmentation and general dryness are seen. At very high doses (several tens Gy), necrotic damage as a result of obliterative endarteritis may cause the eventual loss of limbs or large areas of the skin.

19. TIME OF ONSET OF CLINICAL SIGNS OF SKIN INJURY DEPENDING ON DOSE OF RADIATION EXPOSURE

20. Skin Chronic exposure at lower doses results in hyperkeratosis, characterized by thickening of the epidermis, weekening of the strata with frequent ulceration, poor healing, and decreased vascularization. Chronic exposure is also associated with radiogenic carcinoma, primarily squamous cell carcinoma

21. Mucous Membranes Mucous membranes are also radiosensitive, particularly those in the mouth, pharynx, and esophagus. After considerable doses, dryness, soreness, and petechial ulceration of the mouth occur within 2 weeks. In the third week this progresses to swelling of the tongue with hypersecretion of the mucus, which eventually becomes a thick pseudomembrane that covers the buccal area, throat, and tongue. Later, fibrosis, ulceration, and poor vasculature accompanies skin effects.

22. Central Nervous System Generally, the CNS is resistant to radiation effects. Very high doses are required to cause substantial effects on the brain and nervous system. The vasculature is the limiting factor in radiation effects to the CNS. Effects on the vessels cause breakdown of the capillary circulation with rupture of the walls, interstitial edema, meningitis, encephalitis, and the breakdown of the blood-brain barrier.

23. Central Nervous System At higher doses, prompt killing (pynknosis) of the cerebellum has been seen. At lower doses, reversible changes in neurons can occur. The spinal cord exhibits radiation effects including thickening of the vessels, dissolution of white matter, and myelitis after doses in the order of 5000 R. This is a delayed effect, manifesting one to several years after exposure. Peripheral nerves are highly resistant to radiation effects. Higher doses and longer latent periods are required for expression of effects.

24. The Fetus Fetal effects are seen at relatively low doses of radiation. The fetus is a highly proliferative system with many undifferentiated cells. Therefore it is extremely sensitive to radiation effects. The classic triad of effects of radiation upon the embryo are : 1. Intrauterine growth retardation (IUGR) 2. Embryonic, fetal, or neonatal death 3. Congenital malformation

25. EFFECTS OF RADIATION ACCORDING TO GESTATIONAL STAGE Preconception - No statistically significant effects noted. Preimplantation - “All or none” In the human, implantation of the zygote in the wall of the uterus occurs at approximately days 10 to 12 following conception. Radiation delivered exclusively during this stage may cause prenatal death with failure of implantation; otherwise a normal pregnancy ensues. Implantation - Transient Intrauterine Growth Retardation; threshold 10-20 cGy

26. EFFECTS OF RADIATION ACCORDING TO GESTATIONAL STAGE Organogenesis: 7-13 weeks – Embryo sensitive to lethal, teratogenic and growth-retarding effects because of the criticality of cellular activities and the high proportion of radiosensitive cells. –IUGR, gross congenital malformations, microcephaly and mental retardation are the predominant effects for doses > 50 rads –There is no report of external irradiation inducing morphologic malformation in humans unless the individual also had growth retardation or a CNS anomaly

27. Specific Radiation Effects on the Fetus Mental retardation –Highest risk during major neuronal migration (8-15 weeks). Incidence increases with dose. At 1 Gy (100 rads), 75% experience severe retardation –At 16-25 weeks, fetus shows no increase in mental retardation at doses < 0.5 Gy(50 rads) IQ –Risk factor associated with diminution of IQ is 21-33 points at 1 Gy given in the gestational period 8-15 weeks. Microcephaly: Hiroshima Data –0 dose - 4%; 1-9 cGy - 7%; 10-19 cGy - 11% –20-29 cGy- 23%; 30-49 cGy - 36%; 50-149 cGy 45% –> 150 cGy - 35%

28. Considerations for Pregnancy Termination Normal rate of preclinical loss - > 30%. At 0.1 Gy (10 rads), this is increased by 0.1-1%. Consider the lifetime risk factor for induction of childhood tumors to be 1 in 2000 per cGy. At 5 cGy, maximal risk for childhood leukemia is 1 in 400. Conversely, probability of not having childhood cancer is > 99%. If the fetal absorbed dose > 50 cGy in the 7-13 week window, there is a substantial risk of IUGR and CNS damage. In the range 25 - 50 rads at 7-13 weeks: Parental decision with physician guidance.

29. Lens of the Eye At doses 2-6 Gy, damage to the lens, significant to cause eventual cataract formation. There is no mechanism for removal of cells from the lens. Subsequently, radiation-damaged cells migrate to the posterior poles and centrally, as an opacity. Latent period is from 2-35 years, with a mean time of 8 years at single doses of 2.5-6.5 Gy

30. Other Organs In general the viscera exhibits relative radioresistance. Usually the connective tissue and vasculature become the limiting structures, but functional damage can result from high doses. Lung: Radiation pneumonitis, an acute inflammatory reaction of the functional tissue and vasculature with doses of several thousands centigray after 4 to 6 months. Lung: Radiation fibrosis, accumulation of fibrin in alveoli and septa, 6 months to years after high doses. Blood vessels: Hemorrhage followed by progressive thickening and proliferation of endotelial cells known as obliterative endarteritis. Kidney: Nephrosclerosis, nephritis, hypertension, and renal failure 2 to 3 years after doses of 30 Gy.