development of health risk evaluation data for diagnostic ultrasound: a historical perspective

J Clin Ultrasound 12:493-500, October 1984

Development of Health Risk Evaluation Data for Diagnostic Ultrasound: A Historical Perspective

Harold F. Stewart, PhD, and Roscoe M. Moore, Jr., DVM

Abstract: The growth of ultrasound applications in diagnostic medicine has helped stimulate related biological effects investigations. Current data related to effects associated with diagnostic ultrasound indicate the need for additional research on cell surface structures, motility and developmental effects. Research on biological effects, especially for evaluating in vivo end points analogous to those employed by investigators using in vitro systems and simple organisms, are needed. Particular emphasis relative to potential effects on fetal and embroyonic development is indicated. Limited data also suggest the need to investigate possible effects on the immune response. There is a growing realization of the potential importance of nonthermal effects and increasing evidence that the temporal peak intensity is potentially related to the production of some effects. A number of recent comprehensive reviews have helped identify, analyze and evaluate some of the relevant data. Indexing Words: Biological effeds * Safety

Medical ultrasound imaging was developed from industrial applications and sonar technology used for the detection of submarines during the Second World War. During the 1950s and 1960s, while ultrasound therapy was becoming an established modality, ultrasound for diagnostic use was primarily in the research stage. The first publications describing the diagnostic application of this new technology appeared in the United States in the early 1950~.l-~ "he first device had an A-Mode display and was a modification of an industrial device. This was followed by the development of a B-mode device capable of producing two dimen- sional images of tissue structure^.^.^ Growth in the application of this modality and improvement in its image quality has progressed until it has become an important diagnostic tool. This growth stimulated investigations concerning biological

From the Office of Science and Technology, National Center for Devices and Radiological Health, Food and Drug Adminis- tration, Rockville. MD. Manuscript received September 9, 1983; revised manuscript accepted May 16,1984. For reprints contact Harold F. Stewart, PhD, Division of Physical Sciences, National Center for Devices and Radiological Health, Food and Drug Administration, 12721 Twinbrook Parkway, Rock- ville, MD 20857.

8 1984 by John Wiley & Sons, Inc. 0091 -2751/84/080493-08 $04.00

effects. In this article we will review the history of this research and summarize its current state.

THE HISTORICAL EXPANSION OF EFFECTS RESEARCH

The Center for Devices and Radiological Health (CDRH) published an extensive review of the literature on the measurement, applications and biological effects of ultrasound.6 Considerable ef- fort was expended collecting the scientific literature on the potential health risks associated with ultrasound exposure. Figure 1 is a plot of the cumulative number of papers in our information re- trieval system by year of publication. We consider this a reasonable sampling of the relevant literature. This figure perhaps illustrates the natural growth of health risk information that develops in a scientific community with the use of a new modality. The number of published bioeffects papers increased after the use of ultrasound for therapeutic purposes began in the United States in the 1940s.' The publication of papers continued at about a constant rate from the late 1940s until the 1960s when the rate of publication again increased. This rate coincided with increased research in the diagnostic application of ultra-

493

STEWART AND MOORE

Widespread Use of Diaynostic Ultrasound Begins

Commercial Use 01 Diaynostic Ultrasound Begins

Use 01 Ultraswnd Therapy in the U.S. Begins

1940 1950 1960 1970

Year of Piiblication

flGURE 1. Cumulative number of ultrasound biological effects papers by year of publication.

sound. The first two commercial devices in the United States were an A-Mode echocardiographic unit marketed by Smith-Kline Instruments (Sun- nyvale, CAI and a B scanner marketed by Physi- onics, Inc. (Denver, CO) and both were introduced in 1963.

In 1964, the year following the introduction of commercial ultrasound equipment on the market, the American Institute of Ultrasound in Medicine (AIUM) changed its membership policy. The policy that had limited membership to professionals in physical medicine was expanded to include diagnostic users. Raskind estimated in 1965 that fewer than 500 physicians in the United States had direct experience with the use of diagnostic ultrasound equipment.' Widespread acceptance and application of this modality became evident toward the end of the 1960s. During the 1970s the area of diagnostic ultrasound experienced rapid growth. One study covering the period from 1973 to 1980 reported that the use of diagnostic ultrasound increased at an average annual rate of over 60%' This growth of use resulted in additional interest in bioeffects information. Thus, around 1970 the rate of publication on biological effects again increased with articles in many different journals (Fig. 1). This information some- times resulted from research with emphasis in areas other than the bioeffects of ultrasound. Ex- amples include the initial work reported by Liebeskind et a1.l' which resulted from using ultrasound as part of the control for x-radiation studies on cells. Also Testart et a1.l' reported on premature ovulation in humans after ovarian ultrasonography. These data resulted from research following the timing of follicular maturity in connection with artificial insemination. Other research has been primarily directed at investigating possible effects of ultrasound as used clini-

cally. An example is the report of a trend toward increased fragility of erythrocytes in patients undergoing fetal monitoring using continuous wave Doppler ultrasound for more than 7 hours.12 This effect is also of interest because similar results have been reported in in vitro investigations of the exposure of human erythrocytes to continuous wave ~1trasound. l~ This may be the first example of a potential health effect reported in vitro to be later observed in in vivo studies.

DEVELOPMENT OF BIOLOGICAL EFFECTS DATA

The purpose of this section is to identify some of the types of findings reported. Rather than attempt an exhaustive discussion, selected effects will be discussed to illustrate the nature and character of results that have been obtained with diagnostic type exposures.

From the early 1950s thermal and nonthermal effects were discussed. 13.14 However, emphasis in the late 1950s through the 1970s was largely on thermal mechanisms. Most measurements of exposure were expressed in temporal average values (i.e., total time average power output di- vided by the transducer radiating area), the variable correlated with thermal effects, a mechanism of particular interest in physical therapy. In addition most experimenters were using continuous wave exposure systems. Exposure levels used in physical therapy ranged from time average intensities of 100 mW/cm2 to 3 W/cm2 usually using continuous wave exposure. Diagnostic sources include continuous wave and pulsed Doppler blood flow systems as well as pulse echo imaging systems. Time average intensities from continuous wave Doppler devices are in the range of 1 to 20 mW/cm2. Exposures for diagnostic pulse echo imaging devices are much different having time average intensities ranging from less than 1 mW/cm2 to about 200 mW/cm2 and with peak intensities from less than 1 W/cm2 to in the range of 1000 W/cm2.16 Pulse Doppler exposures have peak intensities similar to those for pulse-echo imaging devices while the spatial peak-time average intensity can range from less than 100 mW/cm2 to over 1 W/cm2. Some research in recent years, particularly as related to pulsed diagnostic ultrasound, has been directed at investigation of cavitation and other nonthermal mechanisms that may be related to the production of biological effects. l7 - l9

One of the first significant biological effects reported with possible implications for diagnostic ultrasound was lower fetal birth weights for the

JOURNAL OF CLINICAL ULTRASOUND

RISK EVALUATION FOR DIAGNOSTIC ULTRASOUND 495

offspring of exposed mice.20 Similar results at various intensities have been reported by several other investigators.21-28 Pursuant to information from animal investigations, Moore et al.29 tested the hypothesis, using data from an exploratory epidemiological study, that lower birth weight would be expected in a human population exposed in utero and obtained a statistically significant association. An independent analysis of these data was performed by the National Institutes of Health consensus development panel.30 They also reviewed the report by Moore et aL2' and one by Stark et al.31 that used the same data base. The panel concluded that there was a significant association between ultrasound exposure with birth weight as reported by Moore et al. The caution that the procedures for matching exposed and un- exposed was possibly not sufficient to have made them comparable in terms of complications that affect bir th~eight .~ ' Other studies need to be con- ducted to examine the generality of this result. Some epidemiological investigations now in progress should provide additional data on this to pi^.^^,^^^^^ The study by Moore et al. represents a turning point in the development of risk assessment data. It was the first time that data from a human diagnostic ultrasound study had been used to test a hypothesis suggested by animal studies.

Another interesting result of the analysis of these data by the consensus panel was the identification of a statistical association of an increased incidence of children with dyslexia exposed in utero in all three hospitals in the study. These results merit further investigations as pointed out in the panel's report. All other developmental parameters measured appeared nor- mal. Dyslexia is a reading disability with the reported probable cause due to some neuronal cells on the left side of the brain not migrating to the proper location when the brain is formed during the 16th to 24th week of gestation.33 Table 1 lists these and other epidemiological investigations of in utero diagnostic ultrasound exposure in humans. There have also been randomized clinical trials that were designed to evaluate the use of ultrasound in management of p r e g n a n ~ y . ~ ~ - ~ ~ These four studies are of limited value for use in the identification and evaluation of potential sub- tle biological effects related to ultrasound exposure. The data in Table 1 suggest the possibility that some effects in humans may be associated with diagnostic ultrasound exposure. However, the data are too limited to confirm or deny in- ferences.

During the 1970s some of the earlier diagnostic

VOL. 12, NO. 8, OCTOBER 1984

TABLE 1 Reported Epidemiological Studies of Human Exposures to Diagnostic Imaging Ultrasound as Related to Safety

~ ~

Type of Exposure Effect Observed References

Diagnostic exami- Reduced birth weight Moore et al.?' nation (human exposed NICHD3'

in utero) (epidemiological study)*

Diagnostic exami- Ultrasound used Hamilton et al.32 nation most often among

women having low birth weight infants (human) (epidemiological study)t

Diagnostic expo- Abnormal grasp re- Schedit et al.,'4 sure for am- flexes, abnormal NICHD" niocentesis tonic neck reflexes

(human)* Diagnostic exami- Dyslexia and reduced Stark et al.?'

nation birth weight (ex- NICHD" posed in utero) (human)*

*Appropriate analysis indicated statistically significant differences between isonofied and non-isonofied groups but due to variations in confounding variables, these differences may not be attributable to ultrasound exposure based on currently available data.

tAuthors point out that significant differences can be expected by chance alone because of the small number of children in the study.

*A more complete analysis of these data is in progress; at this time no conclusions can be drawn because such things as the reason for the ultrasound examination has not been taken into account in this analysis.

equipment was replaced by equipment with better imaging capabilities. Some of this older equipment became available for biological research investigations. Biological effects reported by investigators using such equipment have included a decrease in Drosophila effects on the immune system and the depression of phagocytosis in mice,39,40 effects on cell motility of rat fibroblasts exposed in ~ i t r o , ~ ~ effects on cell surface structure in cultures of mouse fibroblast and rat peritoneal cells,42 disorganization of mi- crotubules in a marine 0rganism,4~,~~ effects on cellular attachment in cultures of kidney am- niotic cells,45 effects related to DNA in cell cul- tUres10,46-48 and detachment of membrane antigens and decreased O2 affinity by erythrocyte^.^^ Reports by these researchers represented an important turn of events in the development of biological effects data because they represented a group investigating new endpoints. For example, a potentially important report at the cellular level is that of Liebeskind et al.41 relative to the persistence in hereditable disturbances in cell motility after exposure to pulsed ultrasound. This may be an endpoint that provides new insight into effects at the cellular level. It also suggests the need for in vivo investigations related to cell migration and cell transformation.

496 STEWART AND MOORE

Frequently, the diagnostic equipment used did not have variable output levels and, thus, did not allow the investigator to obtain exposure response relationships. These new investigators often lacked the equipment to completely measure and characterize the ultrasound fields and the experience to design good exposure arrangements. However, these investigations identified a number of interesting effects. Most of the effects reported using pulse echo diagnostic exposures have not been verified. Some established investigators attempted to find if the effects could be verified under better experimental conditions. For example, Carstensen’s gro~p‘O9~~ repeated some of the work reported by Pizzarella et al.38 using Drosophila. An effect on survival was the only endpoint also observed by Carstensen’s group. However, this follow-up investigation resulted in an increased awareness of the importance of the temporal peak intensity. Saad and Williams52 also reported a depression of phagocytosis using continuous wave exposure at intensities of 600 mW/cm2. This lends credibility to, but cannot be considered a verification of, Ander- son and Barrett’s4’ report of this effect because Anderson and Barrett used a pulsed diagnostic source with a time average intensity of about 9 mW/cm2 and a high temporal peak intensity in the W/cm2 range.

The use of pulse-echo clinical machines provided exposures more closely related to those in actual clinical practice; i.e., microsecond pulses with low average intensities and high temporal peak intensities. The peak intensities from these diagnostic type sources provided exposures where the generation of heat is not usually a mechanism of primary concern, and the peak intensities may be large enough to produce transient cavitation in some cases. Child et al.” indicated that some effects are related to temporal peak intensities and, under certain conditions, may be produced by cavitation. The theoretical bases for associating cavitation with diagnostic type pulses have been developed by F l ~ n n . ’ ~ This model indicates that cavitation may be produced in aqueous media under certain conditions by a single complete cy- cle of microsecond pulse ultrasound. Carstensen and Flynd4 state “Calculations show that inter- nal pressures in the collapsing transient cavities generated by microsecond length pulses are of the order of 1,000 to 70,000 atmospheres and temper- atures are of the order of 1,000 to 10,OOO”C. Shock waves and free radicals generated under these conditions provide both mechanical and chemical mechanisms for biological effects.” Carmichael et al.” reported the production of free radicals in

aqueous solutions exposed to microsecond pulses of ultrasound. However, the production of transient cavitation by diagnostic type pulsed ultrasound in tissue has not been demonstrated.

Some of the earliest data suggesting that temporal peak intensity may be important was that of Taylor and Dy~on.~’ They observed increased abnormalities in chick embryos after in vitro exposure to peak intensities of 25 to 40 W/cm2 but not at peak intensities of 10 W/cm2. Fry et al.56 investigated two exposure conditions, one using a temporal peak intensity of 1900 W/cm2 and the second using a temporal peak intensity of 600 W/cm2.

The exposures were given such that the product of time and intensity were approximately the same. Effects on the fetuses (fetal abnormalities, resorption and litter size) were greater for the higher peak intensity.

Work reported by Takabayashi et al.57358 has also indicated the importance of peak intensity in causing fetal abnormalities. They reported that increased fetal abnormalities in mice were depen- dent on pulse width as well as peak intensity. They observed fetal abnormalities at temporal peak intensities in the range of 60 W/cm2 with pulse widths of 5 and 10 msecs but not with pulse widths of 3 msec.

Some data also suggest that the peak intensity may not be the parameter of primary importance in producing some biological effects. For example, Dooley et al.59 reported that a change in cell survival of rat thymocytes was observed for continuous wave SPTA exposure of 2 W/cm2 but not for a pulsed exposure at the same SPTA intensity. Other research has indicated that the pulse repe- tition frequency is also important in the production of some effects.60*61

EFFORTS TO SUMMARIZE AND ANALYZE AVAILABLE BIOLOGICAL DATA

Attempts have been made by both groups and in- dividuals to review ultrasound biological effects literature. In 1972 Fry and Dunn published exposure-response curves for the adult CNS tissue his- tologically observed threshold and the embryonic CNS tissue functional threshold.62 These are pre- sented in Fig. 2 with other summary curves reported by various investigators over the years.

In 1971, Ulrich completed a literature review to determine the highest ultrasound exposure he believed could safely be used on human subjects.63 This paper was first published as a Navy report and then later in the open literature.a In 1971, a workshop was sponsored by Battelle Memorial In-


MSK EVALUATION FOR DIAGNOSTIC ULTRASOUND 497

& 1 0 3

e a,

h 100 - 0

0 CT 10 v,

.- t

lo’ i

’

z- E 1 0 6 1 U

Fry and Dunn (1971) (lesion thresholds)

Fry ond Dunn (1971)

U

.- t 2 1 o4 1 -TNS functional alterations)

a, C t -

Ulrich (1971)

Wells (19731

- ~I

I Nyborg ( I 977)

N 1 10 100 1 0 3 1 0 4 105

Exposure Time (seconds) FIGURE 2. Biological effects data curves reported by various investigators expressed in terms of spatial average-temporal average (SATA) intensities.

stitute, the National Science Foundation and the Office of Radiological Health to review the ultrasound field and to make recommendations concerning the most pressing problems and studies needed to solve these problems.65 An extensive literature survey was published as part of these proceedings.66 Wells67 reported an extensive literature review of the biological effects data includ- ing a curve shown in Fig. 2 below which no biological effects had been reported. The next published and most widely quoted analysis of biological effects data was by Nyborg.68 Nyborg limited the data to that which he considered applicable to the use of ultrasound in obstetrics. The curve Nyborg developed was expressed in terms of spatial peak temporal average (SPTA) values and was an important step in the recognition that biological effects from diagnostic equipment may be related to spatial peak intensities. For comparison with the other previously published curves, this curve, is also shown in Fig. 2 expressed in terms of SATA values. Nyborg’s analysis was partially based on a thermal model estimating the intensity re- quired for a temperature rise of 2.4”C. This value came from published data by Lele” indicating that a temperature of 2.4”C (above 37°C) repre-


sents a threshold for teratological effects to be produced, especially when maintained over an ex- tended time period. Out of the analysis by Nyborg came the SPTA intensity of 100 mW/cm2 suggesting a lower limit where thermal effects may be important.

Nyborg’s analysis, along with other data, served as a basis for the American Institute of Ultrasound in Medicine’s statement made in Au- gust 1976, revised in October 1978 and reaffirmed in 1982, which reads, “In the low MHz frequency range there have been (as of this date) no inde- pendently [emphasis added] confirmed significant biological effects on mammalian tissues exposed to intensities (SPTA) below 100 mW/cm2. Fur- thermore, for ultrasonic exposure times less than 500 seconds and greater than 1 second, such effects have not been demonstrated even at higher intensities, when the product of intensity and exposure time is less than 50 J / ~ r n ~ . ” ~ ’

There is a growing recognition of the potential importance of nonthermal mechanisms. Addi- tional data published since the development of the curves of Fig. 2 suggest nonthermal effects for some pulsed diagnostic type exposures. These reported effects along with the new theoretical work indicating that cavitation under certain conditions can be produced by a single microsecond pulse suggest the need to report the exposures in terms of temporal peak intensities in addition to other pulse parameters and temporal average values.

The growth and acceptance of diagnostic ultrasound as a valuable and important diagnostic tool in clinical medicine and the increased information concerning biological effects has stimulated several governmental and paragovernmen- tal groups to conduct extensive reviews of the literature and prepare overview reports. This included the National Research Council of Canada,71 the National Center for Devices and Radiological Health (USA),‘ the World Health Organi~ation’~ the National Council on Radiation Protection (USA),73 and a consensus conference sponsored by three components of the National Institutes of Health and the Food and Drug Ad- mini~tration.~’ The consensus conference report in addition to reviewing the literature contrib- uted to the knowledge in this field by performing analyses on some epidemiological data not available to previous groups. It also reviewed the clinical aspects of the use of diagnostic ultrasound. These five reviews serve an important function not only in providing an analysis of available data but in identifying relevant publications for others.

498 STEWART AND MOORE

SUMMARY OF BIOLOGICAL EFFECTS

As a result of the growth of the use of diagnostic ultrasound there is increased interest in biological effects information from the standpoint of mechanisms, animal investigations and human outcome studies. Available data underscore the need for additional bioeffects research, especially investigation of mechanisms by which effects may be produced and the in vivo evaluation of end-points analogous to those used by investigators in in vitro systems and simple organisms. Studies related to changes in cell migration is an example where this seems appropriate. Research directed at elucidating effects as they may relate to fetal and embryonic development and to the immune response deserve special consideration. In addition, independent investigations attempt- ing to verify some effects reported from only one laboratory using pulsed diagnostic type ultrasound would be valuable. Examples include depression of phagocytosis, effects on cell behav- ior and motility, effects on ultrastructure and surface structure of cells and related effects such as detachment of membrane antigens from erythrocytes. Directed research in this area should help us better understand the ability of ultrasound to produce certain biological effects as a function of exposure parameters and ascertain the health risk significance of these effects.

While it is difficult to determine if any specific biological effect observed in experimental studies are likely to occur in the human clinical situa- tion, it is a prudent step in the investigation of possible adverse health effects in humans to follow clues revealed in laboratory and animal studies.

1.

2.

3.

4.

5 .

6 .

REFERENCES

Wild JJ: The use of ultrasonic pulse for the measurement of biological tissues and the detection of tissue density changes. Surgery 27:182, 1950. Wild JJ, Reid JM: Further pilot echographic studies on the histologic structures of tumors of the living intact human breasts. Am J Pathol28:1952. Howry DH, Bliss WR Ultrasonic visualization of soft tissue structures of the body. J Lab Clin Med 40:479, 1952. Thompson HE: The clinical use of pulsed echo ultrasound in obstetrics and gynecology. Obstet Gy- necol Surv 29:903, 1968. Donald I: On launching a new diagnostic science. Am J Obstet Gynecol 103:609, 1969. Stewart HF, Stratmeyer ME: An Overview of U1- trasound Theory, Measurement, Medical Applica- tions, and Biological Effects. USHHS Publication (FDA) 82-8190, NCDRH/AB/DBE, 1982.

7 . Buchtala V: The present state of ultrasonic therapy. Br J Phys Med 153, 1952.

8. Raskind R: Diagnostic ultrasonography. J Am Geriatr Soc 13:887, 1965.

9. Johnson JL, Abernathy DL: Diagnostic imaging procedure volume in the United States. Radiology 146:851, 1983.

10. Liebeskind D, Bases R, Elequin F, et al: Diagnostic ultrasound Effects on the DNA and growth pat- terns of animal cells. Radiology 131:177, 1979.

11. Testart J , Thebault A, Frydman R: Premature ovulation after ovarian ultrasonography. Br J Obstet Gynecol89:694, 1982.

12. Bause GS, Niebyl JR, Sanders, RC: Doppler ultrasound and material eryuthrocyte fragility. Ob- stet Gynecol62:7-10, 1983.

13. Takemura H, Suehara N: The present status of the safety of ultrasonic diagnosis in the area of obstetrics; Studies on the hemolytic effect of clinical diagnostic ultrasound and the growth rate of cultured cells using a calibrated ultrasound generating system. Supersonic Medicine 4:32-36, 1977.

14. Phillips E, Biro LP, Boynton BL, et al: Technical and clinical application of ultrasound energy. Br J Phys Med 17:103,1954.

15. Baldes EJ, Herrick JF, Stroebel CF: Biologic effects of ultrasound. Am J Phys Med 37:lll-121,1958.

16. Stewart HF: Output levels from commercial diagnostic ultrasound equipment. [Suppll. J Ultra- sound Med 2(10) 39,1983.

17. Ter Haar GR, Daniels S: Evidence for ultrasonically induced cavitation in vivo. Phys Med Biol

18. Morton, KI, Ter Haar GR, Stratford et al: Subhar- monic emission as an indicator of ultrasonically- induced biological damage. Ultrasound Med Biol

19. Carmichael AJ, Mosoba MM, Riesz P, et a1 Detec- tion of transient cavitation in aqueous solutions exposed to microsecond pulses of ultrasound. Proc Radiation Res SOC, March 25-29, 1984.

20. O’Brien WD Jr: Ultrasonically induced fetal weight reduction in mice, in Ultrasound in Medicine. New York, Plenum Press, 1976, p 531.

21. Hara K, Minoura S, Okai T, et al: Symposium on recent studies in the safety of diagnostic ultrasound. Safety of ultrasonics on organism. Jpn J Med Ultrasonics 4:256, 1977.

22. Tachibana M, Tachibana Y, Suzuki M. The present status of the safety of ultrasonic diagnosis in the area of obstetrics-The effect of ultrasound irradiation on pregnant mice as indicated in their fetuses. Jpn J Med Ultrasound 4:279, 1977.

23. Pizzarello DJ, Vivino A, Madden B, et al: Effect of pulsed low-power ultrasound on growing tissues. I. Developing mammalian and insect tissue. Exp Cell Biol46:179, 1978.

24. Stolzenberg SJ, Torbit CA, Edmonds PD, et al: Effects of ultrasound on the mouse exposed at different stages of gestation: Acute studies. Radiat Environ Biophys 17:245, 1980.

26: 1145 - 1149,1981.

9~629-633, 1983.


RISK EVALUATION FOR DIAGNOSTIC ULTRASOUND 499

25. Stolzenberg SJ. Torbit CA, Prior GT, et al: Toxicity of ultrasound in mice: Neonatal studies. Radiat Environ Bwphys 18:37, 1980.

26. Stolzenberg SJ, Edmonds PD, Torbit CA, et al: Toxic effects of ultrasound in mice: Damage to cen- tral and autonomic nervous systems. Toxic01 Appl Pharmacol53:432, 1980.

27. Stratmeyer ME, Simmons LR, Pinkavitch FZ: Ef- fects of in utero ultrasound exposure on the growth and developments of mice, in 2nd Meeting of the World Federation of Ultrasound in Medicine and Biology, Miyazaki, Japan, 1979, p 417.

28. Stratmeyer ME, Pinkavitch FZ, Simmons LR, et al: In utero effects of ultrasound exposure in mice, in Abstracts, American Institute of Ultrasound in Medicine Meeting, San Francisco, 1981, p 121.

29. Moore RM, Barrick MK, Hamilton PM: Effects of sonic radiation on growth and development (Abstr). Am Epidemiology 116:571, 1982.

30. National Institute of Child Health and Human De- velopment (NICHD) of the National Institutes of Health (NIHYNational Center for Devices and Radiological Health (NCHRD) of the Food and Drug Administration (FDA): Consensus conference on use of diagnostic ultrasound imaging in pregnancy, February 6-8, 1984.

31. Stark CR, Orleans M, Havercamp AD, et al: Effects of gestational ultrasound exposure on the outcome of pregnancy. Obstet Gynecol 63:194-200, 1984 (also see NICHD consensus conference report Feb-

32. Hamilton PM, Roney PL, Placek PJ, et al: Radia- tion procedures received during pregnancy by mothers of live births and stillbirths: United States, 1980. (Forthcoming publication in Public Health Reports, 1984.)

33. Galaburda A: Developmental dyslexia: Current anatomical research. Ann Dyslexia 33:41-53, 1983.

34. Eik-Nes, SH, Okland 0: Ultrasound screening of pregnant women-A prospective randomized study. NICHD consensus conference, February 6- 8,1984.

35. Bakketig IS, Brodtkorb C, Eik-Nes SH: Screening by ultrasound during pregnancy-A randomized controlled trial. NICHD consensus conference, Feb- ruary 6-8,1984.

36. Wladimiroff JW, Laar J: Ultrasound measurement of fetal body size: A randomized controlled trial. Acta Obstet Gynecol Scand 59:177-179, 1980.

37. Bennett MJ, Little G, Dewhurst J , e t al: Predictive value of ultrasound measurement in early pregnancy: A randomized controlled trial. B r J Obstet

38. Pizzarello DJ, Vivino A, Madden B, e t al: Effect of pulsed low power ultrasound on growing tissues. Expl Cell Bwl46:179-191,1978.

39. Anderson DW, Barrett J T Ultrasound: A new im- munosuppressant. Clin Immuml Immumpathol 14:18, 1979.

40. Anderson DW, Barrett JT: Depression of phagocy-

ruary 6-8, 1984).

Cynec01 80~338-341, 1982.


tosis by ultrasound. Ultrasound Med Biol 7:267, 1981.

41. Liebeskind D, Padawer J , Wolley R, et al: Diag- nostic ultrasound: Time-lapse and transmission electron microscopic studies of cells insonated in uitro. Br J Cancer 45:176, 1982.

42. Liebeskind D, Bases R, Koenigsberg M, et al: Mor- phological changes in the surface characteristics of cultured cells after exposure to diagnostic ultrasound. Radiology 138:419, 1981.

43. Cachon J , Cachon M: Polymorphism of tubulin reassembly in the microtubular system of a heliozoan. 11-cytochemical effects of mechanical shocks and ultrasound. Bwl Cell 40:23, 1981.

44. Cachon J , Cachon M, Bruneton JH: An ultrastruc- tural study of the effect of very high frequency ultrasound on a microtubular system. (Axopods of a heliozoan) Bwl Cell 40:69-71, 1981.

45. Siege1 E, Goddard J , James AE, et al: Cellular attachment as a sensitive indicator of the effects of diagnoetic ultrasound on cultured human cells. Radiology 133:175, 1979.

46. Praaad N, Prasad R, Bushong SC, et al: Ultrasound and mammalian DNA. Lancet 81, 1976.

47. Liebeskind D, Bases R, Mendez F, et al: Sister chromatid exchanges in human lymphocytes aRer exposure to diagnostic ultrasound. Science 206: 1273, 1979.

48. Haupt M, Martin AO, Simpson JL, et al: Ultra- sonic induction of sister chromatid exchanges in human lymphocytes. Hum Genet 59:221, 1981.

49. Pinamonti S, Gallenga PE, Mazzeo V: Effect of pulsed ultrasound on human erythrocytes in vitro. Ultrasound Med Biol 8:631, 1982.

50. Child SZ, Carstensen EL, Lam SK: Effects of ultrasound on drosophila: I11 Exposure of larvae to low-temporal-average-intensity, pulsed irradiation. Ultrasound Med Biol 7:167, 1981.

51. Carstensen EL: Biological effects of low-temporal- average-intensity pulsed ultrasound. Bioelectro- magnetics 3:147, 1982.

52. Saad AH, Williams AR: "he effects of ultrasound on clearance of blood-borne colloidal particles in vivo. Br J Cancer 45:202-205, 1982.

53. Flynn, J: Generation of transient cavities in liquids by microsecond pulses of ultrasound. J Acoust Soc Am 72:1926, 1982.

54. Carstensen EL, Flynn HG: The potential for transient cavitation in pulsed ultrasound (Suppl). J U1- trasound Med 1(7):140, 1982.

55. Taylor KJW, Dyson M: Toxicity studies of the interaction of ultrasound on embryonic and adult tissues, in DeVileger M, White PN, McReady UR (ed): Proceedings of the Second Congress of Ultrasound in Medicine. Amsterdam, Excerpta Medica, 1973, p 353.

56. Fry FJ, Erdman WA, Johnson LK, et al: Ultrasonic toxicity study. Ultrasound Med Biol 3:351, 1978.

57. Takabayashi T, Abe Y, Sato S, et al: Influence of pulse wave ultrasonic irradiation on prenatal development of the m o w . Acta G y d Jpn 31:895,1980.

Mw) STEWART AND MOORE

58. Takabayashi T, Abe Y, Sato S, e t al: Effects of pulse-wave ultrasonic irradiation on mouse embryos. Supersonic Medicine, Special Edition: Stud- ies on the Safety of Pulsed Ultrasound in the Diag- nosis of the Fetus During Pregnancy 8(4):286, 1981.

59. Dooley DA, Child SZ, Carstensen EL, et al: The effects of continuous wave and pulsed ultrasound on rat thermocytes in vitro. Med Biol 9:379-384, 1983.

60. Barnett SB: Bioeffects of pulsed ultrasound. Aust Phys Sci Med 2:397, 1979.

61. Sarvazyan AP, Belousov LV, Petropavlovskaya MN, et al: The action of low intensity pulsed ultrasound on amphibian embryonic tissues. U1- trasound Med Bwl8:639, 1982.

62. Fry FJ, Dunn F: Interaction of ultrasound and tissue, Workshop Proceedings, Interaction of U1- trasound and Biological Tissues, DHEW Publica- tion (FDA) 73-8008, BRWDBE, 1972.

63. Ulrich WD: Ultrasound dosage for experimental use on human beings. Nau Med Res Inst Res Rep 2, 1971.

64. Ulrich WD: Ultrasound dosage for non-therapeutic use on human beings. IEEE Trans Bwmed Eng 21:48, 1974.

65. Reid JM, Sikov MR: Session Introduction, Interac- tion of Ultrasound and Biological Tissues. Work- shop Proceedings, DHEW Publication (FDA) 73-

66. Edmonds PD: Interactions of ultrasound with biological structures-A survey of data. Interac- tion of ultrasound and biological tissues. Workshop Proceedings, DHEW Publication (FDA) 73-8008,

67. Wells PNT: The possibility of harmful biological effects in ultrasound diagnosis, in Reneman RS (ed): Proceedings of the Symposium on Cardiovas-

8008, BRWDBE 73-1, 1972, p 1.

BRH/DBE 73-1, 1972, p 299.

cular Applications of Ultrasound, May 1973. New York, American Elsevier, 1974, p 11.

68. Nyborg WL: Physical Mechanisms for Biological Effects of Ultrasound. HEW Publication (FDA) 78- 8062 (May 1978).

69. Lele P P Ultrasonic teratology in mouse and man, in Proceedings of Second European Congress of Ultrasonics in Medicine. Amsterdam, Excerpta Medica, 1975, p 22.

70. American Institute of Ultrasound in Medicine. Re- port of the AIUM Bioeffects Committee. Reflec- tions 4:330, 1978.

71. Repacholi MH: Characteristics and Biological Ac- tion. National Research Council of Canada Publi- cation NO. NRCC 19244, 1981.

72. World Health Organization. Environmental Health Criteria for Ultrasound. World Health Or- ganization, Geneva, Switzerland, 1982.

73. National Council on Radiation Protection. Biolog- ical Effects of Ultrasound in Medicine. Report of NCRP SC-66. Bethesda, Maryland (Under development).

74. Scheidt PD, Stark F, Bryla DA: One-year follow-up of infants exposed to ultrasound in utero. A m J Obstet Gynecol 131:742-748, 1978. (Also see NICHD consensus conference report, February 6- 8, 1984.)

75. Moore RM: Assessment of Ultrasound Exposure During Gestation and Neonatal Growth. FDA Con- tract No. 223-836023, Johns Hopkins University, 1984.

76. Lyons EA, Coggrave M, Brown RE: Follow-up study in children exposed to ultrasound in utero- Analysis of height and weight in first six years of’ life. Proceedings of 28th Annual Convention, Amer- ican Institute of Ultrasound in Medicine, 49, Sep- tember 15-19, 1980. (Also see “Bioeffect brouha- ha” AIUM bioeffects panel discussion. In Diugnos- tic Imaging 60-63, December 1983.)


development of health risk evaluation data for diagnostic ultrasound: a historical perspective

Documents