BIOLOGIC EFFECT

1. BIOLOGIC EFFECT

2. Contribution to evaluation of biological effects • Development of measurement techniques • Identification of interaction mechanisms • In vitro studies of biologically significant molecules and various cell types • Animal studies with intensities comparable to those used in diagnostic ultrasound • Epidemiologic studies of human populations that will undergone diagnostic ultrasound examination

3. Predictive model • At high intensity it is easy to measure biological effects but for low intensity as used in diagnostic ultrasound it is difficult and need a large number of examination population • Threshold vs non-threshold • If biological effects has a threshold intensity, then below that there would be no effect, but if no threshold necessary then any intensity can carries some risk • Other parameters may have some important effects such as frequency, pulse duration etc.

4. Interaction Of Ultrasound With Matter • Three mechanisms by which ultrasound interacts with matter have been identified: 1. Acoustic radiation force 2. Thermal 3. Cavitation

5. Mechanical Interactions • One mechanism by which damage can be induced, radiation force, is sometimes called direct and generally includes all but thermal and cavitation • When ultrasound interact a particle or interface, the particle or boundary undergo change in velocity and acceleration • The resulting microstreaming or translational movement my cause fragmentation of the macromolecules in the region

6. Thermal Interaction • The second mechanism by which damage can be induced is thermal. • With the ultrasound beam propagation through the medium, its intensity decrease as the sonic energy is absorbed and converted to heat. • The absorption rate depend on biological medium and also ultrasonic field • Absorption of ultrasound in biological materials depend linearly on frequency • Thermal effects dominates in low megahertz frequencies and tend to mask other effects

7. Cavitation Interaction • The third mechanism by which damage can be induced is cavitation. • As the ultrasound wave propagates through the medium, region of compression and rarefaction are created. • Cavitation may be stable or transient • Stable cavitation • In this case microbubbles present in the medium oscillate during application of ultrasonic wave, and hence expand or contract without collapsing • Also may leave the field • At characteristic frequency of the bubbles, the vibration of the neighboring liquid particles is maximize (This condition is called volume resonance) • Biomolecules my rupture as the results of the oscillation of the microbubbles

8. Transient cavitation: It is more violent form of microbubble dynamics in which short lived bubbles undergo large size changes over a few acoustic cycles before completely collapsing • During compression or rarefraction of the wave the bubbles my collapse an create a large temperature (as high as 10/000C) rise or pressure as high as 108 Pascal or higher locally resulting radical formation • The general consensus is that transient cavitation is a threshold effect • The pressure threshold at 1MHz for transient cavitation is about 0.3MPa for optimal radius. At higher frequency more intensity is required. • The threshold for transient cavitation in tissue without preexisting gas nucli is most likely 1500W/cm2 I(SPTP) • Theoretical analysis suggest an I(SPTP) of 1 to 10 W/cm2 for microsecond pulse if microbubble of optimal size is present • It is suggested that a threshold of 0.3MPa at 1MHz is sufficient for microbubble creation. • The threshold increase with f0.5

9. Effect On Biomolecules • The observed biologic effect on mammalian systems exposed to ultrasound is most likely the end product of a long chain of events involving physical, chemical, and physiologic processes. • Inactivation of enzymes in vitro has been demonstrated at very high intensities (eg, 10000W/cm2). • It appears that cavitation is necessary for damage • Degradation of DNA is associated for intensities above 25 to 75 W/cm2 as the results of cavitation

10. Effect On Cells • Cell lyses is caused by cavitation at high intensities levels. • Cell killing has also attributed to microstreaming near cavitation bubbles and to free radical production • Both positive and negative neoplastic transformation of cultured cells has been reported at high intensities • Survival and growth rate for some cell types are reduced following exposure to ultrasound

11. Effects On Mammals • Focal lesions are observed in the brain following exposure when the product of the I(SPTA) and the square root of time for a signal exceeds a threshold of 200Ws0.5/cm2 • The threshold is higher for other organs • Accelerated tissue regeneration has been demonstrated in some cases when injured tissue was subjected to periodic exposure to ultrasound • Little evidence of biologic effect exists for an I (SPTA) of less than 100 mw/cm2, regardless of the duration of exposure. 2

12. Genetic Effects Mutations • In studies with yeast, bacteria, and fruit files exposed to diagnostic levels of ultrasound, no evidence of increased mutation has been observed. • Negative findings at higher intensities were also reported • Kaufman observed mutation in cultured mammalian cell in suspension exposed to 1MHz CW at a spatial peak intensity of 35W/cm2. the mutation was very low and increased by increasing intensity. • Free radical generation in aqueous when exposed to ultrasonic was reported

13. Aberration • MacIntosh and Davey (1970) reported an increase in the frequency of chromatid and chromosomal aberrations of human lymphocytes irradiated in vitro with a fetal heart monitor. • They found a threshold of 8.2mW/cm2 for 1-hour exposure with 2.25MHs • They found opposite results when they repeat the experiments • The results were also in opposite with the results of numerous other investigations • Other investigators also found contrversary results regarding mutation and aberration as the results of diagnostic ultrasound

14. Teratogenic effects • Extensive use of ultrasound during pregnancy and the high sensitivity of embryonic and fetus tissue is well documented • The effects of ultrasound is addressed by two approaches of Experimental and epidemiological • Experimental observations: • Many opposite results both for thermal and non-thermal effects were reported. As the condition of experiments are different a conclusive decision can not be made • Epidemiological study • Surveys of clinical ultrasound users incorporating more than 400000 patients examinations have shown no obvious increase in abnormalities that occur naturally

15. Thermal Damage • Thermal-induced damage is a threshold phenomenon

16. Results of epidemiological studies of ultrasound exposure in uterus

17. In general results of the epidemiological studies have been generally negative, which indicates that damage, if any, is subtle, delayed or infrequent. • The overall assessment is that no firm epidemiologic evidence exists to conclude that a causal relationship exist beteen diagnostic ultrasound and adverse effects

18. AIUM evaluation of bioeffects data • AIUM established a committee to evaluate bioeffects data of ultrasound regularly • The conclusion of the committee are acknowledged to be safety guidelines • In 1976 AIUM committee reviewed all the related data and revised again in 1992. Their conclusion statement is (AIUM,1993):

19. Low MHz frequency range is considered to be 0.5 to 10MHz • CW, PW focused and unfocused beams are included. • The intensity is designated SPTA as measured in free filed conditions • In their very recent statement, very low PRFs (,100Hz) have been excluded, and the intensity of focused beams have been evaluated explicitly. • A diagnostic unit with high PRFs may produce an I(SPTA) above 100mW/cm2 • Most bioeffects are attribute to thermal effects hence temperature rise is critical • The threshold for non mechanical damage is considered a peak pressure of 0.3MPa or mechanical index (MI) of 0.3