Chromosomal deletions

Chromosomal translocations

Outcomes after cell exposure DAMAGE TO DNA DAMAGE REPAIRED CELL NECROSIS OR APOPTOSIS TRANSFORMED CELL

Normal human lymphocyte: chromosomes uniformly distributed

Apoptotic cell: chromosomes and nucleus fragmented and collapsed into apoptotic bodies

Effects of cell death

Coronary angioplasty twice in a day followed by bypass graft because of complication. Dose  20 Gy (ICRP 85) (a) 6-8 weeks after multiple coronary angiography and angioplasty procedures. (b) 16-21 weeks (c) 18-21 months after the procedures showing tissue necrosis . (d) Close-up photograph of the lesion shown in (c). (e) Photograph after skin grafting. (Photographs courtesy of T. Shope & ICRP).

Biological effects of ionizing radiation Deterministic e.g. Lens opacities, skin injuries, infertility, epilation, etc Stochastic Cancer, genetic effects.

Threshold Doses for Deterministic Effects Cataracts of the lens of the eye 2-10 Gy Permanent sterility males 3.5-6 Gy females 2.5-6 Gy Temporary sterility males 0.15 Gy females 0.6 Gy Severity of effect dose threshold

Whole body response: adult 2 1 Acute irradiation syndrome Chronic irradiation syndrome Steps: Prodromic (onset of disease) Latency Manifestation 1-10 Gy Whole body clinic of a partial-body irradiation Mechanism: Neurovegetative disorder Similar to a sick feeling Quite frequent in fractionated radiotherapy 10 - 50 Gy > 50 Gy Survival time BONE MARROW GASTRO INTESTINAL Lethal dose 50 / 30 CNS (central nervous system) Dose

Lethal dose 50 / 30 “Dose which would cause death to 50% of the population in 30 days”. Its value is about 2-3 Gy for humans for whole body irradiation.

Timing of events leading to radiation effects. -15 Energy deposition 10 Excitation/ionization PHYSICAL INTERACTIONS -12 Initial particle tracks 10 Radical formation -9 10 Diffusion, chemical reactions PHYSICO-CHEMICAL INTERACTIONS -6 Initial DNA damage 10 ) c e s ( E -3 10 1 ms DNA breaks / base damage M I T 10 1 second Repair processes Timing of events leading to radiation effects. Damage fixation 3 BIOLOGICAL RESPONSE 10 1 hour Cell killing 1 day Mutations/transformations/aberrations 6 10 Proliferation of "damaged" cells 1 year Promotion/completion 10 9 Teratogenesis MEDICAL EFFECTS Cancer 100 years Hereditary defects

Radiosensitivity [RS] (1) RS = Probability of a cell, tissue or organ of suffering an effect per unit of dose. Bergonie and Tribondeau (1906): “RS LAWS”: RS will be greater if the cell: Is highly mitotic. Is undifferentiated. Has a high cariocinetic future.

Radiosensitivity (2) High RS Medium RS Low RS Bone Marrow Spleen Thymus Lymphatic nodes Gonads Eye lens Lymphocytes (exception to the RS laws) Skin Mesoderm organs (liver, heart, lungs…) Muscle Bones Nervous system

Factors affecting the radiosensitivity Physical LET (linear energy transfer):  RS Dose rate:  RS Chemical Increase RS: OXYGEN, cytotoxic drugs. Decrease RS: SULFURE (cys, cysteamine…) Biological Cycle status:  RS: G2, M  RS: S Repair of damage (sub-lethal damage may be repaired e.g. fractionated dose) % survivor cells  LET  LET G0 M M M G2 G1 S

Systemic effects Which Organ How much Dose Effects may be morphological and/or functional Factors: Which Organ How much Dose Effects Immediate (usually reversible): < 6 months e.g.: inflammation, bleeding. Delayed (usually irreversible): > 6 months e.g.: atrophy, sclerosis, fibrosis. Categorization of dose < 1 Gy: LOW DOSE 1-10 Gy: MODERATE DOSE > 10 Gy: HIGH DOSE Regeneration means replacement by the original tissue while Repair means replacement by connective tissue.

Skin effects Following the RS laws (Bergonie and Tribondeau), the most RS cells are those from the basal stratum of the epidermis. Effects are: Erythema: 1 to 24 hours after irradiation of about 3-5 Gy Alopecia(*): 5 Gy is reversible; 20 Gy is irreversible. Pigmentation: Reversible, appears 8 days after irradiation. Dry or moist desquamation: traduces epidermal hypoplasia (dose  20 Gy). Delayed effects: teleangiectasia (**), fibrosis. Histologic view of the skin From “Atlas de Histologia...”. J. Boya Basal stratum cells, highly mitotic, some of them with melanin, responsible of pigmentation. (*):alopecia: loss or absence of hair (**): ectasia: swelling of part of the body

Skin reactions Threshold Weeks to Injury Dose to Onset Skin (Sv) Early transient erythema 2 <<1 Temporary epilation 3 3 Main erythema 6 1.5 Permanent epilation 7 3 Dry desquamation 10 4 Skin damage from prolonged fluoroscopic exposure Invasive fibrosis 10 Dermal atrophy 11 >14 Telangiectasis 12 >52 Moist desquamation 15 4 Late erythema 15 6-10 Dermal necrosis 18 >10 Secondary ulceration 20 >6

Skin injuries

Skin injuries

Sv single brief exposure Effects in eye Eye lens is highly RS. Coagulation of proteins occur with doses greater than 2 Gy. There are 2 basic effects: Histologic view of eye: Effect Sv single brief exposure Sv/year for many years Detectable opacities 0.5-2.0 > 0.1 From “Atlas de Histologia...”. J. Boya Eye lens is highly RS, moreover, it is surrounded by highly RS cuboid cells. Visual impairment (cataract) 5.0 > 0.15

Eye injuries

Effects of antenatal exposure (1) As post-conception time increases RS decreases It is not easy to establish a cause-effect relation because there are a lot of teratogenic agents, effects are unspecific and not unique to radiation. There are 3 kinds of effects: lethality, congenital anomalies and large delay effects (cancer and hereditary effects). Congenital anomalies % Lethality Pre-implantation Organogenesis Foetus Time

Effects of antenatal exposure (2) Lethal effects can be induced by relatively small doses (such as 0.1 Gy) before or immediately after implantation of the embryo into the uterine wall. They may also be induced after higher doses during all the stages during intra-uterine development. 0.1 Gy % Lethality Time Pre-implantation Organogenesis Foetus

Effects of antenatal exposure (3) Mental retardation: ICRP establishes that mental retardation can be induced by radiation (Intelligence Quotient score < 100). It occurs during the most RS period: 8-25 week of pregnancy. Risks of antenatal exposure related to mental retardation are: 8-15 week 15-25 week Severe mental retardation with a risk factor of 0.4/Sv Severe mental retardation with a risk factor of 0.1/Sv

Delayed effects of radiation Classification: SOMATIC: they affect the health of the irradiated person. They are mainly different kinds of cancer (leukemia is the most common, with a delay period of 2-5 years, but also colon, lung, stomach cancer…) GENETIC: they affect the health of the offspring of the irradiated person. They are mutations that cause malformation of any kind (such as mongolism)