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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 22







     ULTRASOUND





    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the International Radiation Protection Association

    World Health Orgnization
    Geneva, 1982



        ISBN 92 4 154082 6 

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    (c) World Health Organization 1982

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR ULTRASOUND

1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES

    1.1. Summary
         1.1.1. Scope and purpose
         1.1.2. Introduction
         1.1.3. Mechanisms of action
         1.1.4. Biological effects
                 1.1.4.1  Airborne ultrasound
                 1.1.4.2  Molecules in living systems
                 1.1.4.3  Cells in suspension
                 1.1.4.4  Organs and tissues
                 1.1.4.5  Animal studies
                 1.1.4.6  Epidemiology and health risk evaluation
         1.1.5. Exposure limits and emission standards
                 1.1.5.1  Occupational exposure to airborne ultrasound
                 1.1.5.2  Therapeutic use
                 1.1.5.3  Diagnostic use
                 1.1.5.4  General population exposure
    1.2. Recommendations for further studies
         1.2.1. Measurement of ultrasonic fields
         1.2.2. Exposure of patients to diagnostic ultrasound
         1.2.3. Biological studies
         1.2.4. Training and education
         1.2.5. Regulations and safety guidelines for equipment

2. PHYSICAL CHARACTERISTICS OF ULTRASOUND

    2.1. Continuous, gated, and pulsed waves
    2.2. Intensity distribution in ultrasound fields
         2.2.1. Progressive wave fields
         2.2.2. Standing waves
    2.3. Speed of sound
    2.4. Refraction and reflection
    2.5. Characteristic acoustic impedance
    2.6. Attenuation and absorption
    2.7. Finite amplitude effects

3. MECHANISMS OF INTERACTION

    3.1. Thermal mechanism
    3.2. Cavitation
         3.2.1. Introduction
         3.2.2. Stable cavitation
         3.2.3. Transient cavitation and studies concerned
                 with both stable and transient cavitation
         3.2.4. Cavitation in tissues
    3.3. Stress mechanisms
         3.3.1. Radiation pressure, radiation force, and radiation torque
         3.3.2. Acoustic streaming

4. MEASUREMENT OF ULTRASOUND FIELDS

    4.1. Measurement of liquid-borne ultrasound fields
         4.1.1. Measurement of the total power of an ultrasound beam
         4.1.2. Spatial and temporal measurements
    4.2. Measurement of airborne ultrasound fields

5. SOURCES AND APPLICATIONS OF ULTRASOUND

    5.1. Domestic sources
    5.2. Industrial and commercial sources
         5.2.1. Airborne ultrasound exposure levels
    5.3. Medical applications
         5.3.1. Diagnosis
                 5.3.1.1  Exposure levels from diagnostic
                          ultrasound equipment
         5.3.2. Therapy
                 5.3.2.1  Exposure levels from therapeutic
                          ultrasound equipment
         5.3.3. Surgical applications
         5.3.4. Other medical applications
         5.3.5. Dentistry

6. EFFECTS OF ULTRASOUND ON BIOLOGICAL SYSTEMS

    6.1. Introduction
    6.2. Molecules in living systems
    6.3. Cells
         6.3.1. Effects on macromolecular synthesis and ultrastructure
                 6.3.1.1 Protein synthesis
                 6.3.1.2 DNA
                 6.3.1.3 Cell membrane
                 6.3.1.4 Intracellular ultrastructural changes
                 6.3.1.5 Summary
         6.3.2. Effects of ultrasound on mammalian cell
                 survival and proliferation
         6.3.3. Synergistic effects
         6.3.4. Summary
    6.4. Effects on multicellular organisms
         6.4.1. Effects on development
                 6.4.1.1   Drosophila melanogaster
                 6.4.1.2  Mouse
                 6.4.1.3  Rat
                 6.4.1.4  Frog
                 6.4.1.5  Summary
         6.4.2. Immunological effects
                 6.4.2.1  Summary
         6.4.3. Haematological and vascular effects
                 6.4.3.1  Platelets
                 6.4.3.2  Erythrocytes
                 6.4.3.3  Blood flow effect
                 6.4.3.4  Biochemical effects
                 6.4.3.5  Effects on the haemopoietic system
                 6.4.3.6  Summary

         6.4.4. Genetic effects
                 6.4.4.1  Chromosome aberrations
                 6.4.4.2  Mutagenesis
                 6.4.4.3  Summary
         6.4.5. Effects on the central nervous system
                 and sensory organs
                 6.4.5.1  Morphological effects
                 6.4.5.2  Functional effects
                 6.4.5.3  Auditory sensations
                 6.4.5.4  Mammalian behaviour
                 6.4.5.5  The eye
                 6.4.5.6  Summary
         6.4.6. Skeletal and soft tissue effects
                 6.4.6.1  Bone and skeletal tissue
                 6.4.6.2  Tissue regeneration - therapeutic effects
                 6.4.6.3  Muscle
                 6.4.6.4  Thyroid
                 6.4.6.5  Treatment of neoplasia
                 6.4.6.6  Summary
    6.5. Human fetal studies
         6.5.1. Fetal abnormalities
         6.5.2. Fetal movement
         6.5.3. Chromosome abnormalities
         6.5.4. Summary

7. EFFECTS OF AIRBORNE ULTRASOUND ON BIOLOGICAL SYSTEMS

    7.1. Auditory effects
    7.2. Physiological changes
    7.3. Heating of skin
    7.4. Symptomatic effects
    7.5. Summary

8. HEALTH RISK EVALUATION

    8.1. General
         8.1.1. Criteria
         8.1.2. Mechanisms
         8.1.3.  In vitro experimentation
    8.2. Diagnostic ultrasound
    8.3. Therapeutic ultrasound
    8.4. Hyperthermia
    8.5. Dental devices
    8.6. Airborne ultrasound
    8.7. Concluding remarks

9. PROTECTIVE MEASURES

    9.1. Regulations and guidelines
    9.2. Types of standards for ultrasound
         9.2.1. Standards for devices
                 9.2.1.1  Diagnostic ultrasound
                 9.2.1.2  Therapeutic ultrasound
                 9.2.1.3  Other equipment performance standards
         9.2.2. Exposure standards
                 9.2.2.1  Airborne ultrasound

    9.3. Specific protective measures
         9.3.1. Diagnostic ultrasound
         9.3.2. Therapeutic ultrasound
         9.3.3. Industrial, liquid-borne and airborne ultrasound
         9.3.4. General population exposure
    9.4. Education and training

REFERENCES

APPENDIX I

APPENDIX II

APPENDIX III

WHO/IRPA TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ULTRASOUND

 Members

Dr V. B. Bindal, National Physical Laboratory, New Delhi, India

Dr P. D. Edmonds, Ultrasonic Program, Stanford Research
   Institute, Menlo Park, California, USA

Dr D. Harder, Institute for Medical Physics and Biophysics,
   University of Gottingen, Federal Republic of Germanya

Dr K. Lindstr÷m, Department of Biomedical Engineering,
   University Hospital, Malm÷, Sweden

Dr K. Maeda, Department of Obstetrics and Gynaecology, Tottori
   University School of Medicine, Yonago, Japan

Dr V. Mazzeo, Department of Ophthalmology, University of
   Ferrara, Ferrara, Italy  (Vice-Chairman)

Dr W. Nyborg, Department of Physics, University of Vermont,
   Burlington, Vermont, USA

Dr M. H. Repacholi, Radiation Protection Bureau, Department of
   National Health and Welfare, Ottawa, Canada  (Chairman)a

Dr H. F. Stewart, Bureau of Radiological Health, Department of
   Health and Human Services, Food and Drug Administration,
   Rockville, Maryland, USA  (Rapporteur)

Dr M. Stratmeyer, Bureau of Radiological Health, Department of
   Health and Human Services, Food and Drug Administration,
   Rockville, Maryland, USA  (Rapporteur)

Dr A. R. Williams, Department of Medical Biophysics,
   University of Manchester, Manchester, United Kingdom,
    (Rapporteur)

 Representatives of other organizations

Dr W. D. O'Brien, American Institute of Ultrasound in Medicine,
   Department of Electrical Engineering, University of Illinois
   Urbana, Champaign, Illinois, USA

Dr C. Pinnagoda, International Labour Office, Geneva,
   Switzerland
-------------------------------------------------------------------
a Members of the International Non-Ionizing Radiation Committee 
  of IRPA

 Secretariat

Mrs A. Duchŕne, Commissariat Ó l'Energie Atomique, Departement
   de Protection, Fontenay-aux-Roses, Francea

Dr E. Komarov, Scientist, Environmental Hazards and Food
   Protection, Division of Environmental Health, World Health
   Organization, Geneva, Switzerland  (Secretary)

-------------------------------------------------------------------
a Members of the International Non-Ionizing Radiation Committee 
  of IRPA  

NOTE TO READERS OF THE CRITERIA DOCUMENTS                          
                                                                   
    While every effort has been made to present information in the 
criteria documents as accurately as possible without unduly        
delaying their publication, mistakes might have occurred and are   
likely to occur in the future.  In the interest of all users of the
environmental health criteria documents, readers are kindly        
requested to communicate any errors found to the Division of       
Environmental Health, World Health Organization, Geneva,           
Switzerland, in order that they may be included in corrigenda which
will appear in subsequent volumes.                                 
                                                                   
    In addition, experts in any particular field dealt with in the 
criteria documents are kindly requested to make available to the   
WHO Secretariat any important published information that may have  
inadvertently been omitted and which may change the evaluation of  
health risks from exposure to the environmental agent under        
examination, so that the information may be considered in the event
of updating and re-evaluation of the conclusions in the criteria   
documents.                                                         

ENVIRONMENTAL HEALTH CRITERIA FOR ULTRASOUND

    Further to the recommendations of the Stockholm United Nations 
Conference on the Human Environment in 1972, and in response to a 
number of World Health Assembly resolutions (WHA23.60, WHA24.47, 
WHA25.58, WHA26.68) and the recommendation of the Governing Council 
of the United Nations Environment Programme, (UNEP/GC/10, 3 July 
1973), a programme on the integrated assessment of the health 
effects of environmental pollution was initiated in 1973.  The 
programme, known as the WHO Environmental Health Criteria 
Programme, has been implemented with the support of the Environment 
Fund of the United Nations Environment Programme.  In 1980, the 
Environmental Health Criteria Programme was incorporated into the 
International Programme on Chemical Safety (IPCS).  The result of 
the Environmental Health Criteria Programme is a series of criteria 
documents. 

    A joint WHO/IRPA Task Group on Environmental Health Criteria 
for Ultrasound met in Geneva from 7 to 11 June 1982.  Mr G. Ozolins, 
Manager, Environmental Hazards and Food Protection, opened the 
meeting on behalf of the Director-General.  The Task Group reviewed 
and revised the draft criteria document, made an evaluation of the 
health risks of exposure to ultrasound, and considered rationales 
for the development of equipment performance standards and human 
exposure limits. 

    The International Radiation Protection Association (IRPA) 
became responsible for activities concerned with non-ionizing 
radiation by forming a Working Group on Non-Ionizing Radiation in 
1974.  This Working Group later became the International Non-
Ionizing Radiation Committee (IRPA/INIRC) at the IRPA meeting in 
Paris in 1977.  The IRPA/INIRC reviews the scientific literature on 
non-ionizing radiation and makes assessments of the health risks of 
human exposure to such radiation.  Based on the Health Criteria 
Documents developed in conjunction with WHO, the IRPA/INIRC 
recommends guidelines on exposure limits, drafts codes of safe 
practice, and works in conjunction with other international 
organizations to promote safety and standardization in the non-
ionizing radiation field. 

    Two WHO Collaborating Centres, the Radiation Protection Bureau, 
Health and Welfare Canada, and the Bureau of Radiological Health, 
Rockville, USA, cooperated with the IRPA/INIRC in initiating the 
preparation of the criteria document.  The final draft was prepared 
as a result of several working group meetings, taking into account 
comments received from independent experts and the national focal 
points for the WHO Environmental Health Criteria Programme in 
Australia, Canada, Finland, Federal Republic of Germany, Italy, 
Japan, New Zealand, Sweden, the United Kingdom, the USA, and the 
USSR as well as from the United Nations Environment Programme, the 
Food and Agriculture Organization of the United Nations, and the 
International Labour Organisation.  The collaboration of these 
experts, national institutions, and international organizations is 
gratefully acknowledged.  Without their assistance this document 
could not have been completed.  In particular, the Secretariat 

wishes to express its thanks to Dr D. Harder, Dr C. R. Hill, 
Dr M. H. Repacholi, Dr C. Roussell, Dr H. F. Stewart, 
Dr M. E. Stratmeyer, and Dr A. R. Williams for their assistance 
in the preparation of the draft document and to Dr Repacholi and 
Dr Williams for their help in the final scientific editing of the 
text. 

    The document is based primarily on original publications listed 
in the reference section.  Additional information  was obtained from 
a number of general reviews including:  Nyborg, (1977); Repacholi, 
(1981); and Stewart & Stratmeyer (1982). 

    Modern advances in science and technology change man's 
environment, introducing new factors which, besides their intended 
beneficial uses, may also have untoward side-effects.  Both the 
general public and health authorities are aware of the dangers of 
pollution by chemicals, ionizing radiation, and noise, and of the 
need to take appropriate steps for effective control.  The more 
frequent use of ultrasound in industry, commerce, the home, and 
particularly in medicine, has magnified the possibiity of human 
exposure, increasing concern about possible human health effects, 
especially in relation to the human fetus. 

    This document comprises a review of data, which are concerned 
with the effects of ultrasound exposure on biological systems, and 
are pertinent to the evaluation of health risks for man.  The 
purpose of this criteria document is to provide information for 
health authorities and regulatory agencies on the possible effects 
of ultrasound exposure on human health and to give guidance on the 
assessment of risks from medical, occupational, and general 
population exposure to ultrasound. 

    Subjects briefly reviewed include:  the physical 
characteristics of ultrasound fields; measurement techniques; 
sources and applications of ultrasound; levels of exposure from 
devices in common use; mechanisms of interaction; biological 
effects; and guidance on the development of protective measures 
such as regulations or safe-use guidelines. 

    In a few countries, concern about occupational and public 
health aspects has led to the development of radiation protection 
guidelines and the establishment of equipment emission or 
performance standards, and limits for human exposure (mainly to 
airborne ultrasound).  Health agencies and regulatory authorities 
are encouraged to set up and develop programmes which ensure that 
the lowest exposure occurs with the maximum benefit.  It is hoped 
that this criteria document may provide useful information for the 
development of national protection measures against non-ionizing 
acoustic radiation. 

    Details of the WHO Environmental Health Criteria Programme, 
including definitions of some of the terms used in the documents, 
may be found in the general introduction to the Environmental 
Health Criteria Programme, published together with the 
environmental health criteria document on mercury ( Environmental
 Health Criteria 1 - Mercury, Geneva, World Health Organization, 
l976), now available as a reprint. 

1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES

1.1.  Summary

1.1.1.  Scope and purpose

    This document comprises a review of data which are concerned 
with the effects of ultrasound exposure on biological systems and 
are pertinent to the evaluation of health risks for man.  The 
purpose of this evaluation is to provide information for health 
authorities and regulatory agencies on the possible effects of 
ultrasound exposure on human health and to give guidance on the 
assessment of risks from medical, occupational, and general 
population exposure to ultrasound. 

    Subjects briefly reviewed include:  the physical 
characteristics of ultrasound fields; measurement techniques;  
sources and applications of ultrasound; levels of exposure in 
common use;  mechanisms of interaction; and guidance on the 
development of protective measures such as regulations or safe-use 
guidelines. 

1.1.2.  Introduction

    Ultrasound is sound (a mechanical vibration phenomenon) having 
a frequency above the range of human hearing (typically above 16 
kHz) which, unlike electromagnetic radiation, requires a medium 
through which to propagate. 

    Exposure to ultrasound can be divided into two distinct 
categories:  airborne and liquid-borne.  Exposure to airborne 
ultrasound occurs in many industrial applications such as cleaning, 
emulsifying, welding, and flaw detection and through the use of 
consumer devices such as dog whistles, bird and rodent controllers, 
and camera rangefinders, and commercial devices such as intrusion 
alarms.  Liquid-borne exposure occurs predominantly through medical 
exposure in diagnosis, therapy, and surgery. 

    As with any other physical agent, ultrasound has the potential 
to produce adverse effects at sufficiently high doses.  In addition, 
biological effects of unknown significance have been reported under 
laboratory conditions at low exposure levels.  However, the health 
risks that may be associated with biological effects at the levels 
of ultrasound currently encountered in occupational, environmental, 
or medical exposure have not yet been defined. 

    Though, at present, there is no evidence of adverse health 
effects in human beings exposed to diagnostic ultrasound, its 
rapidly increasing use during pregnancy is still of special concern 
in view of the known susceptibility of the fetus to other physical 
and chemical agents. 

1.1.3.  Mechanisms of action

    Acoustic energy may be transformed into several other forms of 
energy, which may exist at the same time within any given medium.  
The mechanisms of transformation into these other forms of energy 
are conventionally subdivided into three major categories 
comprising a thermal mechanism, a cavitational mechanism, and other 
mechanisms including streaming motions. 

    When ultrasound is absorbed by matter, it is converted into 
heat producing a temperature rise in the exposed subject.  An 
ultrasound wave produces alternate areas of compression and 
rarefaction in the medium and the pressure changes produced can 
result in cavitation.  This phenomenon occurs when expansion and 
contraction of nuclei or gas bubbles (in liquids and body tissues) 
cause either simple oscillations or pulsations (stable cavitation), 
or violent events (transient or collapse cavitation), where the 
collapse of the bubbles produces very high instantaneous 
temperatures and pressures.  Theoretical analyses have predicted 
that a single cycle of ultrasound, at a sufficient amplitude level, 
can produce a transient cavitation event in an aqueous medium in 
which appropriate nucleation sites are present.  This prediction has 
not yet been verified experimentally. 

    Streaming motions and shearing stresses can occur within the 
exposed system through stable cavitation; twisting motions 
(radiation torque) have also been observed in biological systems 
exposed to ultrasound. 

    Unlike ionizing radiation, where the basic physical mechanism 
of interaction stays the same with increasing exposure rate, the 
dominant mechanism of ultrasound action on biological systems can 
change as the acoustic intensity, frequency, and exposure 
conditions change. 

    It is generally agreed that diagnostic devices emitting space- 
and time-averaged intensities of the order of a few milliwatts/cm2 
are unlikely to cause temperature elevations in human beings that 
would be regarded as potentially damaging.  It is not known whether 
some form of cavitational activity could occur  in vivo at these 
time-averaged intensities when pulse-echo devices are used.  It has 
been suggested that the elevated temperatures associated with the 
use of higher spatial average temporal average (SATA) intensities 
(0.1-3 W/cm2) contribute to the beneficial therapeutic effects of 
ultrasound.  In addition, gas bubbles have been detected  in vivo 
following therapeutic exposures, indicating that a form of 
cavitational activity has occurred. 

1.1.4.  Biological effects

    Very few systematic studies have been undertaken to determine 
threshold levels for observed effects of ultrasound.  Nearly all of 
the reports in the literature have tended to be phenomenological in 
nature, without evidence from further investigations to determine 
the underlying mechanisms of action.  Furthermore, most reports have 

not yet been confirmed by more than one laboratory.  Some studies 
have been performed using exposure times longer than would normally 
be encountered in the clinical situation and this has made the 
evaluation of health risks from exposure to ultrasound extremely 
difficult.  Thus, there is an urgent need for more carefully 
coordinated, systematic research in critical areas. 

    The health implications from a number of effects already 
reported indicate the need for a prudent approach to the ultrasound 
exposure of human subjects, even though the benefits of this 
imaging modality far outweigh any presumed risks. 

1.1.4.1.  Airborne ultrasound

    Exposure of human beings to low frequency ultrasound (16 -100 
kHz) can be divided into two distinct categories; one is via 
direct contact with a vibrating solid or through a liquid coupling 
medium, and the other is through airborne conduction. 

    For airborne ultrasound exposure, at least one of the critical 
organs is the ear.  Effects reported in human subjects exposed to 
airborne ultrasound include; temporary threshold shifts in sound 
perception, altered blood sugar levels, electrolyte imbalance, 
fatigue, headaches, nausea, tinnitus, and irritability.  However, 
in many instances, it has been difficult to state that the observed 
effects were caused by airborne ultrasound because they were 
subjective and there was often simultaneous exposure to high levels 
of audible sound. 

    The use of experimental animals to study the effects of 
airborne ultrasound has serious drawbacks because they have a 
greater hearing acuity, wider audible frequency range, and a 
greater surface-area-to-mass than man and most have fur-covered 
bodies. 

1.1.4.2.  Biological Molecules

    Studies of the exposure of biological molecules in solution to 
liquid-borne ultrasound have, in general, served to indicate the 
importance of cavitation as a mechanism of ultrasound action and to 
identify which biological molecules preferentially absorb the 
energy.  It is not possible to extrapolate the results of such 
studies to the  in vivo situation. 

1.1.4.3.  Cells in suspension

    There is evidence that ultrasound can change the rate of 
macromolecular synthesis and cause ultrastructural changes within 
cells.  Alterations in cell membrane structure and function have 
been reported from exposure to pulsed and continous wave (cw) 
ultrasound using commercial diagnostic devices. 

    Conflicting results have been reported on the effects of 
ultrasound on DNA. Unscheduled DNA synthesis (indicating possible 
damage and subsequent repair to the DNA) has been reported 
following exposure to pulsed diagnostic ultrasound and cw 
therapeutic ultrasound. 

    Some evidence has been produced that alterations in cell 
surface activity may persist for many generations. 

1.1.4.4.  Organs and tissues

    Studies on skeletal tissue indicate that bone growth may be 
retarded following exposure to ultrasound at high therapeutic 
intensities, even if the transducer is kept in motion during 
treatment.  If the transducer is held stationary, bone and other 
tissue damage occurs at lower intensities. 

    Both  in vitro and  in vivo exposures of muscle tissue have
been reported to trigger contractions.  Therapeutic intensities of 
ultrasound have also been reported to alter thyroid function in 
man.

1.1.4.5.  Animal studies 

    Fetal weight reduction has been observed following exposure of 
rodent fetuses  in utero.  The lowest cw average intensity levels 
that have been observed to induce fetal weight reduction in mice 
are in the low therapeutic range.  Some studies indicate that fetal 
abnormalities and maternal weight loss also occur. 

1.1.4.6.  Epidemiology and health risk evaluation

    To date, adverse effects have not been detected from exposure 
to diagnostic ultrasound.  However, it is of particular concern 
that adequate epidemiological studies have not yet been performed, 
and that soon most human fetuses in technologically developed 
countries could be subjected to at least one ultrasound 
examination.  If such epidemiological studies are not carried out 
very soon, there will not be any "control" populations to 
compare with populations exposed to ultrasound. 

    Most of the human studies that have been performed have 
suffered from inadequate control matching, too few cases, or a 
variety of other problems and though, in general, adverse effects 
have not been reported, these studies are inconclusive and of very 
little value.  The possibility of reduced weight resulting from  in 
 utero exposure, which was reported recently, still needs further 
investigation, especially in light of previous reports of reduced 
body weight in animal fetuses exposed  in utero. 

1.1.5.  Exposure limits and emission standards

1.1.5.1.  Occupational exposure to airborne ultrasound

    Occupational exposure limits for airborne ultrasound have 
already been established or have been proposed in Canada, Japan, 
Sweden, the United Kingdom, the USA, and the USSR.  All standards 
or proposed standards or regulations are similar, in that each has 
a "step" allowing exposure to sound pressure levels above 20 kHz.a

1.1.5.2.  Therapeutic use

    Regulations which incorporate maximum output levels for 
therapeutic ultrasound equipment exist in some countries (e.g., 
Canada) and have been proposed as a requirement by one technical 
sub-committe of the International Electrotechnical Commission. 
Other countries, such as the USA, have not incorporated a limit on 
output levels in their ultrasound therapy products standard. 

1.1.5.3.  Diagnostic use

    Given the current biological and biophysical data base, there 
does not appear to be sufficient information to establish 
quantitative limits on output levels for diagnostic ultrasound 
equipment. 

1.1.5.4.  General population exposure

    Ultrasound is used in many consumer products (e.g., camera 
range-finders and TV controls, burglar alarms etc.) but little is 
known about their potential health effects in the general 
population, although they are thought to be negligible. 

1.2.  Recommendations for Further Studies

1.2.1.  Measurement of ultrasonic fields

    One of the difficulties of establishing a comprehensive body of 
information with respect to the biological and health effects of 
ultrasound has been the lack of adequate instrumentation to measure 
the various exposure parameters.  However, reliable methods for the 
measurement of ultrasound field parameters, such as total radiated 
power, and the various intensities in the ultrasound fields, are 
now available in a few national or research institutions. 

    Most devices used to measure ultrasound power and the various 
temporal and spatial intensity parameters for liquid-borne        
ultrasound are not suitable for routine surveys in the work place.
There is an urgent need for the development of portable, rugged   
instrumentation that will measure accurately both total power and 
the relevant intensity parameters.                                
---------------------------------------------------------------------------
a The International Radiation Protection Association is proposing 
  guidelines on limits of exposure to airborne acoustic energy for 
  both workers and the general population.


                                                                  
    Furthermore, a substantial research effort is still needed to 
develop a system of dosimetric variables relevant to the production 
of and protection against adverse health effects of ultrasound in 
medical and industrial applications. 

1.2.2.  Exposure of patients to diagnostic ultrasound

    Information concerning the ultrasound exposure of patients 
during diagnostic examinations has often not been available in the 
past.  Manufacturers are now increasingly supplying diagnostic 
ultrasound equipment together with appropriate data to enable users 
to evaluate the level to which the patient is exposed, and to 
decide which devices would give the lowest exposure commensurate 
with good diagnostic quality.  This trend is commendable and should 
be strongly encouraged. 

    Until the potential health effects of exposure to ultrasound 
have been properly evaluated, it is recommended that manufacturers 
should aim at keeping the output levels necessary for examinations 
as low as readily achievable.  This priority should apply to all 
diagnostic techniques where the exposure time required to conduct 
the examination can be minimized. 

    It is strongly recommended that patients should only be exposed 
to ultrasound for valid clinical reasons. 

1.2.3.  Biological studies

    Most bioeffect studies have been conducted on cell suspensions, 
plants, insects, and other animal systems.  However, it should be 
noted that some of these biological systems accentuate certain 
mechanisms of interaction to the extent that effects are observed 
under exposure conditions that would not apply to, or would not 
induce effects in human beings.  Controversy continues as to the 
exact mechanisms by which the effects of ultrasound are induced.  
It is often possible to distinguish between dominant thermal and 
non-thermal mechanisms, but the type of non-thermal effect remains 
open to discussion.  Cavitation is a well established mechanism of 
action, but other non-thermal mechanisms may be involved in the 
production of some ultrasound effects.  With more complete 
information on biological and physical mechanisms, studies can be 
undertaken to determine possible thresholds (if they exist) for 
bioeffects and the biophysical knowledge could be used to predict 
potential bioeffects. 

    (a) Molecules and cells

    It is recommended that studies be conducted at both the 
molecular and cellular levels on interactions between ultrasound 
and biological systems.  Such information is needed to evaluate the 
importance of the interaction mechanisms involved and to clarify 
areas and end-points that need further study at higher levels of 
biological organization. 

    (b) Immunological studies

    Recent studies suggest that ultrasound may induce immunological 
responses in laboratory animals.  Because of the fundamental 
importance of the immune system, any effects that might be induced 
by ultrasound should be systematically investigated. 

    (c) Haematological studies

    Ultrasound at therapeutic intensities has been shown to cause 
platelet aggregation and other haematological alterations  in vitro.
Results of some studies suggest that similar effects may occur  in 
 vivo.  This suggestion needs to be investigated further to assess 
possible adverse consequences  in vivo.

    (d) Effects on DNA

    Recent studies reporting repair to DNA, observed as unscheduled 
DNA synthesis, need to be substantiated.  Of particular importance 
is the investigation of damage to DNA from pulsed ultrasound with 
intensities in the diagnostic range. 

    (e) Genetic effects

    Reports of sister chromatid exchanges, increased transformation 
frequency, and changes in the cell membrane and cell motility, seen 
many generations after a single exposure to ultrasound, suggest a 
"genetic" effect.  Because these results have not been adequately 
confirmed, they cannot, at present, be extrapolated to the  in vivo 
situation; and need further investigation. 

    (f) Fetal studies

    A number of reports indicate that lower fetal weight and 
increased fetal abnormalities occur following exposure to 
ultrasound in the low therapeutic intensity range.  Studies should 
be undertaken to establish exposure thresholds (if any) for effects 
on the fetus exposed on various days during gestation.  The 
importance of the ratio of temporal average to temporal peak 
intensities in relation to the production of fetal effects also 
needs considerable investigation. 

    Since gross effects appear to occur only at high ultrasound 
intensities, research workers should concentrate their efforts on 
subtle effects, particularly in the fetus, which in many instances 
receives a whole-body exposure to ultrasound.  Wherever possible, 
studies should be related to clinical situations. 

    Only one study on human beings suggests that lower birthweights 
may result from exposure to diagnostic ultrasound  in utero. 

    As the practice of ultrasound diagnosis becomes more 
widespread, it will be difficult to find adequate control 
populations and opportunities for satisfactory epidemiological 
studies may become increasingly rare.  It is strongly recommended 
that cost-effective, well-designed studies be conducted soon and 
coordinated at both the national and international levels. 

    Short-term studies where specific end-points, such as 
haematological effects, can be identified, also need to be 
conducted.  Investigations should be made on patients undergoing 
ultrasound therapy, since the average intensities used are 
significantly higher than those used in diagnosis.  To date, such 
studies do not seem to have been undertaken. 

    (g) Behavioural studies

    Studies on rodents suggest that behavioural effects may be seen 
in newborn that have been exposed  in utero.  If these studies are 
confirmed, systematic studies on human newborn will be necessary, 
to determine whether such effects occur in man. 

    (h) Synergism

    It is common for patients to undergo diagnostic examinations, 
on the same day, in both the ultrasound and X-ray departments of 
hospitals.  Some evidence has been produced indicating that X-rays 
may enhance ultrasound effects.  Increased chromosome aberration 
rates in somatic cells have been observed following combined 
exposure to ultrasound and X-rays.  Preliminary reports also 
suggest that ultrasound may have a synergistic action with such 
agents as heat, viruses, and drugs.  Such synergistic effects need 
to be investigated further. 

    (i) Airborne ultrasound

    Few studies have been reported on the effects of airborne 
ultrasound on man.  Earlier reports of headaches and nausea seem to 
have been largely attributed to subharmonics of the ultrasound beam 
in the audible range.  However, there has been a number of reports 
of similar symptoms from people exposed to devices such as 
ultrasound intrusion alarms.  This indicates that further 
investigation in this area is necessary. 

1.2.4.  Training and education

    Since the ultrasound exposure levels currently employed in 
physiotherapy are well within the range in which adverse health 
effects have been confirmed, it is recommended that all operators 
of such equipment receive formal training (up to l year) before 
treating patients.  These operators should also ensure that their 
equipment is properly maintained and calibrated to make sure that 
patients receive only the prescribed "dose". 

    Operators of diagnostic ultrasound equipment should also 
receive appropriate formal training on the use and safety of this 
clinical modality.  They should be properly instructed on 
maintaining and calibrating the equipment to ensure that the 
ultrasound exposure of the patient is minimized while maximizing 
the quality of the image. 

    In commercial, industrial, and research establishments where 
devices emitting airborne and/or liquid-borne ultrasound operate, 
all potentially exposed employees should be properly instructed 
with regard to safety precautions appropriate for the equipment 
being used. 

    Consumers using devices that emit airborne ultrasound should 
familiarize themselves with the safety precautions provided by the 
manufacturer. 

1.2.5.  Regulations and safety guidelines for equipment

    Protective measures include the use of either mandatory 
standards (regulations) or guidelines on equipment emission and 
performance. 

    Where appropriate, safety guidelines should be provided for 
operators of equipment that emits airborne ultrasound.  In many 
cases, such guidelines should recommend the use of hearing-
protectors and appropriate warning signs. 

    As surveys indicate, many ultrasound therapy devices do not 
give the output levels indicated on the control console, so 
mandatory standards or regulations are recommended for this type of 
equipment.  Such standards should include accuracy specifications 
for the output power, output intensity, and timer setting. 

    The establishment of guidelines on the performance of 
diagnostic ultrasound equipment is recommended and these should 
include requirements concerning the image quality and stability, 
and quality assurance measures.  At present, there does not appear 
to be a need to limit the output exposure levels of diagnostic 
ultrasound equipment, other than to recommend strongly that the 
lowest output levels be used commensurate with image quality, 
adequate to obtain the necessary diagnostic information. 

2.  PHYSICAL CHARACTERISTICS OF ULTRASOUND

    Ultrasonic energy consists of mechanical vibrations occurring 
above the upper frequency limit of human audibility (generally 
accepted as about 16 kHz).  Ultrasound consists of a propagating 
disturbance in a medium, which causes subunits (particles) of the 
medium to vibrate.  The vibratory motion of the particles 
characterizes ultrasonic (acoustic) energy propagation.  Unlike 
electromagnetic radiation, acoustic energy cannot be transmitted 
through a vacuum.  The transmission through the medium depends to a 
great extent on the ultrasound frequency and the state of the 
medium, i.e., gas, liquid, or solid. 

    Ultrasound may propagate in different modes.  In solids, two 
important modes include compressional (longitudinal) waves and 
shear (transverse) waves (Fig. 1).  The propagation velocities of 
these two modes are generally different. 

FIGURE 1

    Ultrasound propagates in gaseous, liquid, or solid media, 
mainly in the form of longitudinal or compressional waves formed by 
alternate regions of compression and rarefaction of the particles 
of the medium, which vibrate in the direction of energy 
propagation.  The distance between two consecutive points of 
maximum compression or rarefaction is called the wavelength. 

    Transverse (shear) waves mainly propagate in solids, and are 
characterized by particle displacement at 90░ to the direction of 
propagation.  At a bone/soft tissue interface, one type of wave can 
give rise to another (mode conversion).  If a longitudinal wave 
propagating in soft tissue strikes bone at an angle, both 
longitudinal and transverse waves may be excited in the solid 
medium.  This phenomenon can result in heating at the bone surface. 
Results of heating in bone have been reported by Lehmann & Guy 
(1972) and Chan et al. (1974). 

    The passage of a sound wave through a medium can be 
characterized by several variables, associated with the movement of 
particles in the medium.  These include:  acoustic pressure ( p), 
particle displacement (xi), particle velocity ( v), and particle 
acceleration ( a). Under idealized conditions each of these 
quantities varies sinusoidally with space and time (Appendix I). 



    The acoustic pressure ( p) is the change in total pressure at     
a given point in the medium at a given time, resulting in compression
where  p is positive, and expansion where  p is negative, as a         
result of the action of the ultrasound waves.  The displacement (xi) 
is the difference between the mean position of a particle in the     
medium and its position at any given instant in the time ( t).  The   
particle velocity ( v) is the instantaneous velocity of a vibrating   
particle at a given point in the medium.  This should not be confused
with the speed of sound ( c).  The latter is the speed with which     
the wave propagates through the medium, even though the individual   
particles of the medium vibrate only about their mean positions with 
no bulk movement of matter.  The speed of sound ( c) is a constant    
that depends on the physical properties of the medium; it is         
discussed in section 2.3.  As a result of the sinusoidal variation 
in particle velocity ( v), each particle experiences an acceleration 
( a) which also varies with time and position; it has positive 
values when  v increases, and negative values when  v decreases. 

    The relationship between the intensity and various particle 
parameters such as acoustic pressure, displacement, velocity, and 
acceleration (Appendix I, Table 1) may be of importance when 
analysing some biological effects reported in the literature. 

    For comparative purposes, it is worth noting an important 
difference between ionizing radiation and ultrasound.  To increase 
the intensity of a beam of X-rays of a given spectral distribution, 
the photon flux is increased.  The energy of each individual photon 
remains unchanged.  Therefore, the interaction mechanism for each 
photon remains the same, but the number of interactions per unit 
time increases because of the increased number of photons.  To 
increase the intensity of a beam of ultrasound of fixed frequency, 
the amplitude of the particle parameters (pressure, displacement, 
velocity, acceleration) is increased, to obtain a higher energy 
flux per unit area.  Change in the magnitude of the particle 
parameters may affect the relative importance of different 
mechanisms of interaction with matter at different intensities. 

2.1.  Continuous, Gated, and Pulsed Waves               
                                                                    
    The differences between continuous wave, gated (amplitude-      
modulated), and acoustic-burst pulsed waves are shown in Fig. 2.  A 
continuous wave at a single frequency is a simple sinusoidal wave   
having constant amplitude.  Amplitude-modulated waveforms are used  
in some equipment, for example, pulsed therapy equipment.  An       
acoustic burst is the type of pulse used in pulse echo diagnostic   
equipment.  It can represent the variation of pressure as a function
of distance at a fixed instant in time, or as a function of time at 
a fixed point in space.  For the pulsed wave, the pressure amplitude
is not constant and is zero for part of the time.  No acoustic      
energy is being emitted between pulses and the ultrasound           
propagates through the medium as small packages of acoustic energy. 
Pulsed waves can have any combination of on/off times.  Thus, it is 
important to specify exactly the time regimen of the pulsed beam.   

FIGURE 2

    Pulsed ultrasound with short and widely-spaced pulses         
(typically microsecond (Ás) pulses spaced at intervals of 
milliseconds (ms) is used for diagnostic purposes, whereas 
continuous waves (cw) are often used in therapeutic applications  
of ultrasound and in most Doppler devices.  Though the temporal 
(time) average of the sound intensity produced by a diagnostic 

pulse echo machine is usually about 1000 times less than the 
intensity in a therapeutic ultrasound beam, the acoustic pressure 
and the particle displacement, velocity, and acceleration during  
the pulse may reach peak values an order of magnitude greater than 
those in cw therapeutic ultrasound.                               

     A particular complex time structure of the ultrasound field 
may occur with real-time diagnostic devices that have an array of 
transducers, where acoustic beams emitted by adjacent elements of 
the array sequentially contribute to the acoustic intensity at a 
point in space.  The temporal characteristics of ultrasound fields 
such as pulse duration, pulse repetition frequency, and temporal 
peak intensity have been reported by several investigators 
(Barnett, 1979;  Child et al., 1980a; Lewin & Chivers, 1980; 
Sarvazyan et al., 1980).  A distinction must be made between the 
spatial peak intensity and the spatial average intensity (Appendix 
I, Table 1); great differences between particle parameters can 
occur over space as well as time.  Considerable spatial variations 
in pressure occur in a standing wave field (section 2.2.2). 

2.2.  Intensity Distribution in Ultrasound Fields

    Many of the ultrasound fields encountered during exposure of 
human subjects, or in related biological studies, may be quite 
complex, but most can be considered to be somewhere between two 
extreme types:  the progressive wave field and the standing wave 
field.  In the first case, it is possible to define and measure a 
flux of energy along the direction of propagation in terms of any 
of the four parameters ( p, xi,  v,  a) (Appendix I, Table 1). 

2.2.1.  Progressive wave fields

    The ultrasonic field produced by a transducer obeys all the 
physical laws of wave phenomena.  It can be thought of as being 
produced by many small point sources making up the transducer face 
and thus producing a characteristic interference pattern at any 
point in the field.  As ultrasound is propagated from the transducer, 
there is a zone where the overall beam size remains relatively 
constant (the near field), though there are many variations of 
intensity within the zone itself, both across and along the beam 
axis.  This zone is followed by a zone where the beam diverges and 
becomes more uniform (the far field).  Fig. 3 illustrates the near 
field (or Fresnel region) with the transition into the far field 
(or Fraunhofer region) for cw operation.  For a circular piston 
source of diameter D radiating sound of wavelength lambda, the 
Fresnel zone extends from the transducer to a distance equal to 
D2/4 lambda (when D is much greater than lambda); beyond this 
distance is the Fraunhofer zone of the transducer.  A numerical 
analysis of the near field of a vibrating piston has been described 
in the literature (Zemanek, 1971).  For a given radius of the 
transducer, the near field becomes more complex (exhibiting more 
maxima and minima) as the wavelength of the ultrasound becomes 
shorter.  The acoustic field of a pulsed transducer can be thought 
of as being composed of contributions from all the frequencies 
within the bandwidth of a short pulse.  It has been shown (Wien & 

Harder, 1982) that the near field is less structured than that of a 
cw transducer, and that the length of the near field corresponds to 
that of a cw transducer oscillating at the centre frequency of the 
pulsed field. 

FIGURE 3

    In the far field of any transducer, the acoustic intensity 
is proportional to the square of the acoustic pressure.  The 
directivity of the beam in the far field is determined by 
diffraction, in the same way that a light wave is affected by a 
small aperture; the higher the frequency of ultrasound produced for 
a given transducer size, the more directional is the beam.  Further-
more, if the frequency is held constant but the diameter is reduced, 
the beam divergence increases.  Equation 2.1 is the formula for 
conveniently determining the angle of divergence (theta) in the far 
field (Kinsler & Frey, 1962) as shown in Fig. 3. 

    Sin theta = 1.22 lambda/D                          Equation 2.1

    For the diagnostic transducers used for pulse echo imaging 
purposes, the beam width determines the minimum lateral resolution 
that can be expected.  For this reason, many diagnostic transducers 
are focused to decrease the beam width and enhance lateral 
resolution. 

    The intensity distribution along the axis of such a transducer 
is such that an axial intensity peak occurs at some distance from 
the transducer.  This peak is a common feature of both focused and 
nonfocused fields, and its existence is an important factor in 
characterizing ultrasound fields and in the interpretation of some 
of the biological data.  The ultrasonic intensity at this highest 
main axial peak of the field is referred to as the spatial peak 
intensity of the field.  For exposure in experimental studies, the 
spatial peak intensity may refer instead to the local maximum, 
within the exposed region.  It is also possible to define a spatial 
average intensity as the ratio of the power to the beam cross-
sectional area, in the plane of interest.  The definition of beam 
cross section (Appendix II) allows a choice of the amplitude at the 
lateral margin of the beam.  Therefore, values of spatial average 
intensity will depend on this choice and caution should be 
exercised when comparing reports from different laboratories. 

    For a theoretical plane circular piston source in an infinite 
non-reflecting medium, the spatial maximum intensity in the near 
field is 4 times greater than the spatial average intensity at the 
transducer surface (Zemanek, 1971; Nyborg, 1977).  In actual 
practice, this ratio typically has values ranging from about 2 to 6 
for unfocused transducers, though higher values may be encountered, 
depending on such factors as the nature of the piezoelectric 
material used and how it is mounted in the applicator housing 
(Stewart et al., 1980). 

    The intensity of the ultrasonic field produced by the 
transducer also varies with time, if the ultrasound is pulsed. 
Intensity averaging can be carried out in the time domain and it is 
therefore necessary to distinguish between time (or "temporal") 
average (such as the average over the total time or over the pulse 
duration) and temporal peak intensities (Appendix II). 

2.2.2.  Standing waves

    Standing waves can occur when cw ultrasound is propagating into 
a confined space, so that the ultrasound waves are reflected back 
from an interface and travel past each other in opposite directions.
This may be the case, for example, within a small room or in a 
small container of water in the absence of absorbing materials.  
The resultant waveform, at any instant, is obtained by adding the 
wave pressures at each point.  The acoustic energy distribution is 
characterized by a stationary spatial pattern with minima and 
maxima of pressure amplitude, called "nodes" and "antinodes", 
respectively.  Under the conditions applied during medical diagnosis 
and therapy (generally in the range 1-10 MHz), a progressive wave 
field usually predominates, though there may be an appreciable 
standing wave component if, for example, there is a bone/tissue or 
tissue/gas interface within the beam.  The possibility of the 
occurrence of standing waves is usually of less importance with 
pulsed ultrasonic irradiation, because they can only exist during 
the pulse overlap time at a given spatial location. 

2.3.  Speed of Sound

    The speed ( c) at which ultrasonic vibrations are transmitted 
through a medium is inversely proportional to the square root of 
the product of the density (rho) and the adiabatic compressibility 
( B) of the material, such that  c = (rho B)-0.5.  The speed 
together with the frequency ( f) of the ultrasound determine the 
wavelength lambda (lambda =  c/f) of the waves that are propagated. 
For example, the propagation velocity of ultrasound in most human 
soft tissues ranges from approximately 1450 to 1660 m/s, so that 
frequencies of 1 MHz correspond to a wavelength in the range of 
1.4-1.7 mm respectively.  Thus, ultrasonic diagnostic imaging 
procedures carried out in this frequency range have the potential 
for providing resolution of the order of 1 mm.  Knowledge of the 
speed at which ultrasound is transmitted through a medium is used 
in diagnostic applications for the conversion of echo-return time 
into the depth of tissue being imaged.  Values of sound speed for 
some other media of interest are given in Table 1 which shows that 
the speed of sound is highest in solids, somewhat lower in liquids 
and soft tissues, and very much lower in gases. 

2.4.  Refraction and Reflection

    When an ultrasound wave encounters an interface between two 
media, the dimensions of which are large compared with the wave-
length, part of the wave will be reflected back into the first 
medium with the same speed.  The rest of the wave will be 
transmitted or refracted into the medium beyond the interface and 
will travel with the velocity of propagation in that medium (Fig. 
4).  For reflection, the angles of incidence (thetai) and 
reflection (thetar) are equal; for transmission the angles of 
incidence and refraction are generally unequal.  When the 
ultrasonic wavelength is equal to or greater than the dimensions of 
the reflecting object, the incident beam is scattered in all 
directions. 

    The ratio of the characteristic impedances ( Zo) of any two
media on either side of an interface (see the following section) 
determines the degree of reflection and refraction or transmission 
of the incident wave. 

2.5.  Characteristic Acoustic Impedance

    The characteristic acoustic impedance of a medium is the
product of the density (rho) and the speed ( c) of sound in that
medium.  The extent to which ultrasonic energy is transmitted or 
reflected at an interface separating two continuous isotropic media 
is determined by the ratio of the characteristic acoustic 
impedances of the media.  The closer this impedance ratio is to 1, 
the more energy is transmitted into the second medium and the less 
is reflected from the interface.  At an interface between human 
tissue and air, only about 0.01% of the incident energy is 
transmitted, the remainder being reflected.  This illustrates the 
importance of using a coupling medium between the transducer and 
human tissue for both therapeutic and diagnostic ultrasound 

applications. Strong reflections (close to 50%) also occur at 
bone/tissue interfaces; thus bone/tissue and tissue/gas interfaces 
constitute an important limitation on the accessibility of some 
human anatomical regions to diagnostic ultrasonic investigation. 

FIGURE 4

2.6.  Attenuation and Absorption

    As an ultrasound beam is transmitted through a heterogeneous 
medium such as soft tissue, its intensity is reduced or attenuated 
through a number of mechanisms, including beam divergence, 
scattering, absorption, reflection, diffraction, and refraction. 

    Beam divergence refers to the spreading of the beam in the far 
field through diffraction effects (section 2.2.1).  For a given 
transducer radius, this phenomenon is greater at lower frequencies. 
As the beam area becomes larger, the intensity is reduced. 

    Scattering refers to the reflection of the incident ultrasound 
from interfaces (i.e., surfaces separating media of different 
characteristic acoustic impedances) with dimensions close to or 
less than the ultrasound wavelength.  In this case, the incident 
beam is scattered in all directions.  Ultrasound impinging on blood 
cells, for example, would be scattered.  When scattering occurs, it 
is greater at higher ultrasonic frequencies. 

    Absorption of ultrasound occurs when the ordered vibrational 
energy of the wave is dissipated into internal molecular motion, 
i.e., into heat.  There are many mechanisms by which ultrasound 
absorption occurs in a medium, including viscous loss, hysteresis 
loss, and relaxation processes. 

    The acoustic pressure amplitude  px of the progressive
ultrasound wave of initial acoustic pressure amplitude  po, at
a distance x for a nondiverging beam, in any uniform medium,
is described by the relationship:

     px =  poe-alphax                                    Equation 2.2

where e is the base of natural logarithms and alpha is the 
amplitude attenuation coefficient of the medium (as defined in 
Appendix I) for a given frequency.  Alpha is a measure of the rate 
at which an ultrasonic wave decreases in amplitude as a function of 
distance by other than geometric means as it propagates through a 
medium.  For any given medium, a increases with increasing 
frequency.  Because the acoustic intensity is proportional to the 
square of the acoustic pressure, attenuation can be expressed also 
in terms of intensity: 

     Ix =  Ioe-2alphax                                   Equation 2.3

    Attenuation is important from several points of view.  First, 
it results in a decrease in intensity at various depths in the 
medium and determines the amount of acoustic energy that can reach 
structures of interest, either for imaging or therapeutic purposes. 
Second, attenuation by scattering can result in ultrasonic energy 
reaching unintended structures.  Third, attenuation is important, 
because it is due in part to an absorption process in which the 
propagating energy is permanently modified (for example, converted 
into heat energy which causes a temperature rise in tissue).  In 
therapeutic applications, energy absorption and heat generation in 
tissue are usually the intended results. 

    Attenuation is greater in some soft tissues than in others.    
This variation is exploited in therapy for differential absorption 
and heating of ligaments and tendons in surrounding muscular tissue
(Lehmann et al., 1959; Stewart et al., 1982).                      

    Because of the depth of penetration desired, the frequencies    
used for therapy purposes range from about 0.5 to 3 MHz.  For       
diagnostic purposes, the upper limit of the range for imaging in    
abdominal areas is about 10 MHz.  Frequencies up to 20 MHz are used 
for small structures such as the eye, which have a lower attenuation
coefficient and shorter imaging depth.                              

    Absorption is considerably higher in bone than in soft tissues. 
This is one reason why bone may constitute a critical organ for     
some forms of ultrasonic exposure, especially ultrasound therapy,   
even though there is a strong reflection from a bone/soft tissue    
interface.  Bone damage has been reported in experimental animals   
(Barth & Wachsmann, 1949; Kolar et al., 1965) at levels just higher 
than those normally employed in physiotherapy (i.e., 3-4 W/cm2)     
(section 6.4.6).  In addition, ultrasound exposure of a bone/tissue 
interface can result in sudden and sometimes pronounced periosteal  
pain arising from a buildup of heat at the interface.  At the 
bone/tissue interface, some of the longitudinal oscillations 
(particles  oscillating in the direction of propagation) are 

transformed into transverse oscillations.  The transverse 
oscillations (shear waves) are more readily absorbed than 
longitudinal waves.  This can produce local heating at the 
bone/tissue interface causing periosteal pain (Lehmann et al., 
1967).                             

2.7.  Finite Amplitude Effects

    Another effect that may be important when ultrasound is applied 
in biomedical research, diagnosis, or surgery results from the 
finite amplitude of the particle velocity of the ultrasonic wave-
front.  In linear acoustics, two familiar assumptions are made: 
(a) that the transmitted frequency is the only frequency produced; 
and (b) that when the input amplitude is increased, the amplitude 
at remote points in the field increases proportionally.  These 
linear assumptions are not valid when considering finite-amplitude 
effects.  For a more detailed explanation, the reader is referred 
to Beyer & Letcher (1969). 

    It has been shown (Beyer & Letcher, l969; Muir & Carstensen, 
1980; Carstensen et al., 1981) that the frequencies and intensities 
used in pulsed diagnostic ultrasonics can potentially create 
significant distortion of sound waves in water. 

Table 1.  Typical values of ultrasonic properties of various media at 
1 MHz.
--------------------------------------------------------------------------
                              Characteristic               Amplitude
Medium            Ultrasonic  acoustic       Attenuation   absorption
                  speeda      impedanceb     coefficientc  coefficient
                   c            Zo=rho x c     alpha         alpha a
                  (m/s)       (103 kg/s m2)  (Np/cm)       (Np/cm)
--------------------------------------------------------------------------
air (dry)         343.6       0.45           0.18          0.18
(20░C)

water (37░C)      1480        1480           0.0002        0.0002
                                                                 
amniotic fluid    1530-1540   1540-1560      0.0008        ND

aqueous humour )  1530-1540   1540-1560      0.005-0.08    ND
vitreous humour)

blood )           1555-1525   1560-1580      0.001-0.002   ND
plasma)

testis                                       0.03-0.04     0.01-0.02

fat               1450-1490   1360-1400      0.07-0.24     ND

liver )
kidney)           1560-1600   1580-1620      0.07-0.3      0.02-0.05
brain )
heart )

spleen  )         1510-1600   1580-1620      0.07-0.3      ND
pancreas)

muscle            1560-1600   1620-1700      0.06-0.16     ND

uterus            1600-1660                  0.02-0.20     ND

lens              1600-1660                  0.02-0.20     ND

skin  )           1720-2000                  0.04-0.50     ND
tendon)

bone              3000-3300   4000-7000      1.3-3         ND

lung              500-1000                   2-3           ND
--------------------------------------------------------------------------
Note:   These values are for animal tissue and are for illustrative
        purposes only; published data are not always consistent.  Actual 
        measured values may show quite strong variability with factors 
        such as tissue preparation temperature and intensity.
a Velocity of longitudinal waves.                     ND = not determined
b Estimated from published data.
c Attenuation is approximately proportional to frequency: alpha=alpha1 fm, 
where alpha1 is the attenuation coefficient at 1 MHz,  f is the frequency 
in MHz, and known values of m lie between 0.76 (tendon) and 1.14 (brain).

3.  MECHANISMS OF INTERACTION

    When acoustic energy is absorbed by matter, it is converted 
into heat, the consequent temperature elevation depending on the 
amount of energy absorbed, the specific heat of the medium, and the 
dynamic balance between heat deposition and removal.  In contrast 
to X-rays, for example, commonly used ultrasound beams can carry 
appreciable amounts of energy and thus one mechanism of action of 
potential biological importance is thermal.  A second phenomenon 
that is well known to be associated with ultrasonic energy, and to 
play a major role in many of the biological changes that have been 
induced by ultrasound applied  in vitro, is cavitation.  However, 
not all the evidence of biological and biochemical changes induced 
by ultrasound can be explained on the basis of either heat or 
cavitation.  It is necessary to be aware of a further group of 
established and/or physically predictable stress mechanisms, and of 
the possible existence of other biophysical mechanisms, hitherto 
undocumented.  Finally, it should be noted that the different 
mechanisms, as classified in this manner, are not necessarily 
independent; for example, the biological expression of a physical 
stress directly induced by the passage of ultrasound may well be 
influenced by the temperature of the irradiated structure.  Examples 
of reviews of ultrasound mechanisms are those published by Nyborg 
(1977, 1979, 1982) and Repacholi (1981). 

3.1.  Thermal Mechanism

    Several reviews concerning the elevation of temperature 
resulting from ultrasound exposure have been published (Lele, 1975; 
Nyborg, 1977). 

    When ultrasound interacts with matter, part of the energy of 
the beam will be absorbed and converted into heat.  The rate (Q) at 
which heat is generated per unit volume within a medium is given by 
the equation Q=2 Iaalpha a; where alpha a is the amplitude absorption
coefficient of the medium and  Ia is the intensity of a plane 
travelling ultrasound wave (Appendix I).  Without heat conduction 
away from the exposed site, the rate of temperature rise will be 
(Dunn, 1965): 

    d T/d t = 2alpha a Ia/rho Cm                            Equation 3.1

    where d T/d t is the temperature rise per unit time, rho is the 
ambient density of the medium, and  Cm is the specific heat per unit 
mass.

    Consider an example of soft tissue exposed to an ultrasound 
beam of intensity 1 W/cm2.  If rho = 1 g/cm3,  Cm = 1 cal/g/░C and 
alpha a is 0.1 Np/cm, the temperature rise d T/d t is then 0.048░C/s, 
when heat conduction is neglected. 

    If the effect of heat conduction away from exposed matter is 
considered, it will be appreciated that, following an initial rise, 
the temperature will tend towards an equilibrium value.  Calculations 
covering this behaviour for a spherical model have been given by 

Nyborg (1977); some results are shown in Fig. 5.  For this model 
(a spherically symmetrical object exposed in an isotropically 
conducting medium), the increase in equilibrium temperature is 
proportional to the square of the radius, as is the time required 
to attain that temperature.  Thus, a small body uniformly exposed 
to ultrasound will experience a small but rapid temperature rise, 
whereas a large body, uniformly exposed to the same ultrasound 
intensity, will reach a higher final temperature, but over a longer 
period of time.  It follows that temperature elevations resulting 
from local heating on a scale comparable to cellular dimensions 
(10-50 Ám), which presumably occurs as a result of local absorption 
mechanisms, will be insignificant in practice.  This conclusion was 
reached independently by Love & Kremkau (1980). 

FIGURE 5

    In practice, the biological expression of heat-induced damage   
is found to depend both on the maximum temperature achieved and on  
the time period for which that temperature is maintained.  According
to Lele (1975), exposure of mice to a temperature elevation of 
2.5 - 5.0░C for an hour or more during pregnancy caused a 
significant increase in the number of fetal abnormalities.                      


                                                                    
3.2.  Cavitation

3.2.1.  Introduction

    Under certain conditions, the application of ultrasound to a 
liquid (or quasi-liquid) medium gives rise to activity involving 
gaseous or vaporous cavities or bubbles in the medium.  This 
phenomenon, termed cavitation, may require pre-existing nuclei, 
i.e., bodies of gas with dimensions of the order of micrometres 
or smaller which are stabilized in crevices or pores, or by other 
means, in the medium.  Reviews of the subject have been given by 
Flynn (1964), Coakley & Nyborg (1978), Neppiras (1980), and Apfel 
(1981). 

    It has proved useful (Flynn, 1964) to distinguish between 
stable and transient cavitation.  Both of these are important 
mechanisms for biological effects of ultrasound, the former being 
especially relevant at lower intensity levels (e.g., 300 mW/cm2 
or less in water) and the latter at higher levels.  In many 
experiments, both types of cavitation occur simultaneously, but in 
certain situations only stable cavitation occurs. 

3.2.2.  Stable cavitation

    In some media, gas bubbles exist which are of such a size 
that they are resonant in the sound field and oscillate with large 
amplitude.  When a bubble expands and contracts during the 
ultrasound pressure cycle, the surrounding medium flows inwards and 
outwards with a higher velocity than if the gas bubble were absent. 
As a rough guide, the resonant diameter of a cavitation bubble in 
water at 1 MHz is about 3.5 Ám.  Alternatively, gaseous nuclei may 
exist in the medium which are initially smaller than resonance size 
but which grow to that size in an applied sound field through the 
process of rectified diffusion. 

    When a gas bubble pulsates, its motion is not usually 
spherical, either because of distortion by an adjoining boundary 
or because of surface waves set up by the ultrasound field.  
Asymmetric or non-uniform oscillation of the air-liquid interface, 
at the surface of an air pocket or bubble, causes a steady eddying 
motion to be generated in the immediately adjoining liquid, often 
called microstreaming, in which the velocity gradients may be high.  
If biopolymer molecules or small biological cells are suspended in 
liquid near a pulsating bubble, they may be swept into a region of 
high velocity gradient.  Such a situation can also occur if a small 
bubble pulsates near a cell membrane causing the membrane to 
vibrate, producing streaming motions within the cell.  The 
biological system will then be subjected to shearing action and 
damage may occur, such as fragmentation of macromolecules and 
membranes (Nyborg, 1977). 

    Significant biological effects occur in suspensions near 
resonant bubbles, even at low spatial peak temporal average (SPTA) 
intensity levels.  For example, Barnett (1979), and Miller et al. 
(1979) found that blood platelets tended to aggregate around 

artificial holes (forming gas bubbles) in a membrane, and Williams 
& Miller (1980), using similar membrane material (containing gas-
filled pores) observed ATP release from red blood cells.  All of 
these effects were observed at SPTA levels considerably lower than 
0.1 W/cm2. 

    These findings are consistent with the theory of microstreaming 
and with experimental information on the response of biological 
cells to hydrodynamically generated viscous stress (Glover et al., 
1974; Brown et al., 1975; Anderson et al., 1978; Dewitz et al., 
1978, 1979).  For example Nyborg (1977) estimated that a bubble of 
3 Ám radius in blood plasma, caused to pulsate by ultrasound at an 
intensity of 1 mW/cm2 with a frequency of about 1 MHz (to which the 
bubble is resonant), would generate a microstreaming field in which 
the maximum viscous stress would greatly exceed 100 N/m2. The 
latter is an intermediate value for hydrodynamically generated 
viscous stress which causes cell lysis. 

    Pulsating bubbles also produce microstreaming in organized 
tissues.  Martin et al. (1978) reported acoustic streaming motions 
in plant and mammalian systems, using Doppler fetal heart monitors 
under experimental conditions that ensured the existence of gas 
bubbles.  According to Akopyan & Sarvazyan (1979), streaming can 
produce changes in the relative positions of intracellular 
organelles and breaks in cytoplasmic structures. 

3.2.3.  Transient cavitation and studies concerned with both
stable and transient cavitation

    In contrast to stable cavitation, transient (or collapse) 
cavitation is more violent and occurs at higher ultrasound 
intensity levels.  When a gas bubble or nucleus within the 
medium is acted on by an ultrasound field having a high pressure 
amplitude, it may expand to a radius of twice the original value or 
more, then collapse violently.  In the final stages of collapse, 
kinetic energy given to a relatively large volume of liquid has to 
be dissipated in an extremely small volume, and high temperatures 
and pressures result.  Idealized thermodynamic calculations show 
that for a compression in which no heat escapes from the cavity at 
the end of the cavity's existence, the final temperature is around 
8000 K and the pressures are greater than 109 Pa (104 
atmospheres).  Of course, the idealized assumption of a 
thermodynamically closed system is not valid under such extreme 
conditions.  Sutherland & Verrall (1978) report that, under actual 
conditions, not all the heat remains trapped in the cavity during 
collapse; some is conducted away, resulting in estimated 
temperatures of the order of 3500 K.  It seems reasonable to 
assume that effects on biological systems may be induced at least 
by the mechanical shock waves and high temperatures generated 
during the bubble collapse. 

    Chemical changes are commonly produced by cavitation.  The 
combination of high pressures and temperatures can generate aqueous 
free radicals and hydrated electrons (highly reactive chemical 
species) within the exposed medium by the dissociation of water 
vapour in the bubble during its contraction.  Chemical interactions 

of biomacromolecules with these free radicals often result 
(especially with hydrogen H- and hydroxyl 0H- radicals), and 
significantly alter their properties.  This can be accompanied by 
the formation of such compounds as nitrous acid (HNO2), nitric acid 
(HNO3), and hydrogen peroxide (H2O2) (Akopyan & Sarvazyan, 1979). 

    Studies show that transient cavitation does not occur unless 
the intensity exceeds some threshold value which is very dependent 
on experimental conditions.  The cavitational threshold SPTA 
intensity was determined by Esche (1952) and Hill (1972a) for 
frequencies ranging from 0.25 to 4 MHz, in air-equilibrated water, 
for cw ultrasound.  The threshold intensity was in the range of a 
few watts per square centimetre and was frequency dependent.  The 
higher the frequency, the higher the intensity required to produce 
cavitation. 

    Pulsing conditions have a marked influence on cavitation.  
Hill & Joshi (1970) found that, at shorter pulse durations, the 
cavitation threshold increased.  Alternatively, as the pulse 
duration decreased, the duty factor had to be increased to 
produce cavitation at a given intensity.  A model for acoustic 
cavitation, according to which cavitation activity is optimized for 
an appropriate choice of pulsing parameters, has been postulated 
and confirmed experimentally by Ciaravino et al. (1981). 

    Higher ambient pressure causes higher threshold intensities for 
cavitation.  For a cw 1 MHz ultrasound beam, Hill (1972a) found 
that the threshold intensity varied from just under 1 W/cm2 at an 
ambient pressure of 105Pa (1 bar) to much greater than 16 W/cm2 at 
1.75 x 105Pa (1.75 bar).  Increasing the ambient pressure often 
provides an effective means of inhibiting cavitation and thereby 
ascertaining whether a previously observed response was due to 
cavitation. 

    It has also been found that the threshold for cavitation 
decreases with increasing temperature (Connolly & Fox, 1954) and 
with increasing volume of the irradiated liquid (Iernetti, 1971). 

    Particularly important for the occurrence of cavitation is the 
number and size distribution of gas nuclei within the medium. 
Unfortunately, these quantities are not easily measured.  The 
number of available nuclei within a fluid medium greatly increases 
when the medium is stirred or mechanically disturbed (Williams, 
l982a). 

3.2.4.  Cavitation in tissues

    Intracellular gas channels are commonly present in plant 
tissues and greatly influence the biological response of these 
tissues to ultrasound (Nyborg et al., l975; Carstensen, 1982). 
Similarly, the responses of insects and insect eggs to ultrasound 
are greatly influenced by the presence of microscopic airpores 
(Child et al., 1980a, 1981a, 1981b).  A characteristic of the 
response of both plants and insects to pulsed ultrasound is that 
the critical exposure parameter appears to be the temporal peak 
rather than the temporal average of the intensity. 

    Much less is known about cavitation in mammalian tissues.  In a 
series of studies, Fishman (1968) was unable to detect significant 
levels of haemolysis in the blood of human volunteers whose hands 
were immersed in an 80 kHz cleaning bath for up to 45 min.  However, 
the external ears of rabbits developed numerous petechial haemmorrhages 
when they were immersed for more than 3 min in a 55 kHz cleaning 
bath (Carson & Fishman, 1976). 

    Lehmann (1965a), using dogs, reported that tissue damage, which 
was attributed to cavitation, occurred at intensity thresholds of 
1-2 W/cm2 for 1 MHz ultrasound applied by means of a stationary 
applicator.  When a stroking technique was used, these effects were 
not observed at intensities up to 4 W/cm2.  A dependence on ambient 
pressure, observed for this biological effect is a strong indication 
that the gas content of the tissue was involved in the reaction. 
Thresholds of about 1.5 W/cm2 have been reported for soft tissue 
damage due to cavitation caused by exposure to cw ultrasound with 
the transducer in a stationary position (Hug & Pape, 1954).  On the 
basis of morphological findings and physical measurements, they 
concluded that cavitation could be expected in tissues at 
intensities in the range used for therapeutic purposes.  Similar 
data have also been reported by Lehmann & Herrick (1953).  Other 
reports of effects on experimental animals also indicate that 
cavitation may have been responsible (O'Brien et al., 1979; Martin 
et al., 1981). 

    Evidence for the existence of gaseous nuclei in tissues has 
been given by ter Haar & Daniels (1981).  They observed that the 
production of gas bubbles in the legs of guinea-pigs exposed to 
cw 0.75 MHz ultrasound at SATA intensities of 80 and 680 mW/cm2, 
was associated with tissue interfaces.  At 680 mW/cm2, sites 
occurred throughout the entire cross-section of the leg with many 
bubbles located intramuscularly.  The rate of appearance of sites 
increased with both intensity and duration of exposure.  The 
authors reported that an SATA intensity of 80 mW/cm2 appeared to be 
close to an intensity threshold for stable bubble production in 
tissues  in vivo.  In applying the theory for rectified diffusion to 
these results, Crum & Hansen (1982) showed that they were 
consistent with an assumption that gaseous nuclei with diameters in 
the range of a few micrometres exist normally within tissues. 

3.3.  Stress Mechanisms

    Stress mechanisms or non-thermal, non-cavitational mechanisms 
of ultrasound action have been reviewed by Nyborg (1977) and Dunn & 
Pond (1978).  Ultrasound exposure produces various stresses within 
biological systems, the magnitude and significance of which depend 
on the detailed characteristics of the ultrasound field and the 
biological system exposed.  Lewin & Chivers (1980) proposed a 
viscoelastic model of the cell membrane as a potential means of 
investigation in connection with pulsed sources.  Repacholi (1982) 
found evidence that many biological effects on cell systems  in 
 vitro may be due to forces both within and outside the cell, which 
might be mediated by stress mechanisms. 

    Stresses or forces resulting from an ultrasound field acting on 
heterogeneous regions within a medium can be categorized as follows 
(Dunn & Pond, 1978): 

    (a) buoyancy forces that are oscillatory, have a time-
        average equal to zero, and produce a radiation
        pressure on bodies having a density different from
        the surrounding medium;

    (b) displacement or radiation forces that have a non-
        zero time average and can cause an appreciable
        relative velocity between the inhomogeneity and the
        surrounding medium;

    (c) viscosity-variation forces or viscous stresses that
        result in acoustic streaming because of variations
        in viscosity over the cycle of the applied ultrasound;
        and

    (d) the Oseen force, another time-averaged force, which
        is due to the dependence of drag on the second power
        of relative velocity.

3.3.1.  Radiation pressure, radiation force, and radiation torque

    There is evidence of radiation pressure (from ultrasound 
pulses) being detected by the inner ear and giving rise to 
disturbances that can be sensed by the brain as if they were 
audible sound (Foster & Wiederhold, 1978).  In addition, Gershoy & 
Nyborg (1973) postulated that gradients of radiation pressure in 
exposed plant tissue give rise to water flow in cytoplasmic 
channels. 

    An example of the action of radiation force is the blood flow 
stasis phenomenon reported by Dyson et al. (1971), where red blood 
cells in the blood vessels of chick embryos exposed to an 
ultrasonic standing-wave field, collected into parallel bands 
spaced at half wavelength intervals.  This has also been shown in 
mammalian vessels (ter Haar et al., 1979). 

    Spinning of intracellular bodies exposed to highly non-uniform 
ultrasound fields has been observed by various investigators (Dyer, 
1965, 1972; Nyborg, 1977; Martin et al., 1978).  When an ultrasound 
field is propagated within a liquid, a twisting action may be 
exerted on suspended objects, and on elements of the liquid itself. 
For an asymmetrically shaped object such as a rod or disc, this 
radiation torque varies with the orientation of the object relative 
to the oscillation direction of the surrounding liquid, so that the 
object tends to assume the position in which the torque on the 
object is least.  Such an effect may be important, when the effects 
of ultrasound on asymmetrically shaped cells, organelles, or 
macromolecules are considered.  For a symmetrical object, steady 
spinning will result.  Theoretically, this spinning is expected in 
non-uniform fields such as those existing at a boundary where a 
progressive ultrasound wave impinges obliquely and is reflected 
(Nyborg, 1977).  In the latter situation, the object's velocity of 

spinning ( v) is proportional to the ratio of the absorption 
coefficient (alpha a) for the material in this spherical body and to
the coefficient of shear viscosity (eta) for the surrounding fluid. 

    Martin et al. (1978) observed the effects of radiation torque 
in sonicated (2.1 MHz, 43 mW/cm2) leaves of  Elodea and root tips of 
 Vicia faba.  How radiation torque affects other macromolecular 
structures or organelles within or outside cells is not known, at 
present. 

3.3.2.  Acoustic streaming

    When an ultrasound field is propagated within a liquid, the 
particles of the liquid take part in an oscillatory flow.  Consider 
a particle oscillating in a direction parallel to a boundary.  At 
the boundary itself, the velocity of the liquid flow will be zero 
provided the boundary is a fixed, rigid solid, and "non-slip" 
conditions apply.  Conditions may then exist for establishing 
acoustic streaming, a time-independent circulatory motion of the 
liquid.  As part of this motion a thin boundary layer may exist 
between the surface and the streaming liquid itself, within which 
the velocity gradient is large.  Such streaming has been observed 
as circulatory flow in the vacuoles of plant cells (Nyborg, 1978). 
However, there must be non-uniformity or some kind of asymmetry for 
this streaming to be established.  For an ultrasound field 
propagating in a suspension of particles, relative motion occurs 
between the particles and the fluid, where boundary layers are 
established around each particle and give rise to an acoustic 
streaming field.  Such microstreaming was demonstrated near 
vibrating gas bubbles by Elder (1959), who analysed four regimes of 
streaming. 

    Early effects attributed to acoustic streaming were reported by 
Nyborg & Dyer (1960), who demonstrated the migration of protoplasm 
towards a needle vibrating at 25 kHz in intact cells of  Elodea.  
Selman & Jurand (1964) described the disorganization and subsequent 
recovery of the arrangement of the endoplasmic reticulum following 
irradiation for 5 min with 1 MHz ultrasound at intensities between 
8 and 15 W/cm2.  More recently, these stresses associated with 
acoustic streaming have been suggested to be responsible for: 

    (a) altered cell surface charge (Repacholi, 1970;
        Repacholi et al., 1971; Taylor & Newman, 1972);

    (b) altered cell membrane permeability (Chapman, 1974;
        Chapman et al., 1980; Al-Hashimi & Chapman, l981);

    (c) separation of small fragments from cells (Dyson et
        al., 1974; Nyborg, 1979; ter Haar et al., 1979);

    (d) rupture and fragmentation of cell membranes (Williams,
        1971; Brown et al., 1975; ter Haar et al., 1979); and

    (e) reduced uptake of radioactive precursor in mammalian
        cells  in vitro (Repacholi, 1980).

4.  MEASUREMENT OF ULTRASOUND FIELDS

    The spatial distribution of ultrasound fields can be quite 
complicated depending on such factors as focusing, the radius of 
the transducer, the wavelength of the ultrasound, the distance from 
the source, and even on the way in which the element of the 
transducer is mounted (Zemanek, 1971).  Any effect produced by 
ultrasound will depend quantitatively on the temporal and spatial 
characteristics of the ultrasonic field.  It is therefore necessary 
to consider the methods available for making physical measurements 
to determine the relationships between the equipment output levels 
used in human exposure and the results of biological studies. 

    These methods are divided into measurement techniques for 
liquid-borne and airborne ultrasound.  Several extensive reviews of 
techniques for measuring liquid-borne ultrasound have been reported 
in the literature (Stewart, 1975, 1982; Zieniuk & Chivers, 1976). 
The phenomenon of solid-borne ultrasound, for example, in bone (Fry 
& Barger, 1978) is also of interest, but will not be dealt with 
here. 

4.1.  Measurement of Liquid-borne Ultrasound Fields

    Measurements necessary to characterize ultrasound fields should 
include all spatial and temporal characteristics.  This will involve 
measuring at least one (and possibly more) of the four field 
parameters ( p, xi,  v, a), discussed in section 2, over all relevant 
conditions of space and time.  Once these parameters are known, it 
is possible to calculate the spatial and temporal behaviour of 
power and intensity in the equivalent plane-wave field.  In order to 
characterize exposure, the total power should be specified as well 
as the following intensities:  spatial average temporal average 
(SATA) intensity; spatial peak temporal peak (SPTP) intensity; 
spatial peak temporal average (SPTA) intensity; and, if applicable, 
spatial peak pulse average (SPPA) intensity and spatial average 
pulse average (SAPA) intensity.  These and other factors that are 
important for the complete characterization of ultrasonic exposure 
in the investigation of biological effects are summarized in Table 2. 

    Acoustic power and intensity have traditionally been used to 
express exposure.  They are the parameters specified in most 
standards, e.g., the AIUM-NEMA (1981) standard, the Japanese 
standards for diagnostic equipment (JIS 1979, 1980, 1981; JAS, 
1976, 1978), and the standards of Canada (Canada, Department of 
National Health and Welfare, 1981) and the USA (US Food and Drug 
Administration, 1978) for the performance of ultrasound therapy 
equipment. 

    Relatively little work has been carried out concerning         
ultrasonic field measurements in tissue, though some measurements  
and theoretical calculations to determine the ultrasonic field in  
tissue have been reported (Chan et al., 1974).  Instrumentation    
used for internal field measurements include thermocouples for the 
measurement of temperature rise at specific locations (Goss et al.,
1977) and miniature transducers inserted into bodies (Bang, 1972;  
Lewin, l978).                                                      

Table 2.  Biologically important exposure parameters
---------------------------------------------------------------------
(a) Continuous wave (cw) ultrasound

    Frequency of ultrasound
    SATA intensity
    SPTA intensity (if focused)

(b) Pulsed ultrasound

    Centre frequency
    Pulse shape or frequency spectrum
    Pulse duration
    Pulse repetition frequency or duty factor
    Frame repetition frequency (automatic scanners)
    
    SPTP intensity
    SPPA intensity
    SPTA intensity

(c) General

    Exposure time
    Exposure fractionation (if not a single exposure)
    Degree and periodicity of the modulation or interruption
    Single transducer
    Transducer diameter
    Array dimensions (automatic scanners)
    Type of field (focused or unfocused)
    Focal area, focal length (if focused)
    Other details of geometric conditions, such as:
    Exposure under far-field or near-field conditions
    Acoustic path length to organ or site of interest
    Extent of standing wave component (if any)
    Relation of the peak to the average intensity for
     the beam cross section of interest, (i) if the source is
     maintained in a fixed position and orientation during exposure;
     (ii) if not fixed, the path and speed of motion
---------------------------------------------------------------------

    Reported measurements of the attenuation between the abdominal 
surface and the uterine cavity are shown in Table 3. 

    Instruments available for measuring liquid-borne ultrasound   
include those that measure total power and those that can measure 
point quantities over an area.  With the latter, it is possible to
determine the distribution of the energy in the ultrasonic field. 


Table 3.  Reported attenuation between the abdominal surface and the 
uterine cavitya
------------------------------------------------------------------------------
No.       Average      Attenuation  Distance  Frequency  Species  Reference
patients  rate of      (dB)         (cm)      (MHz)          
          attenuation                         
          (dB/cm)                                            
------------------------------------------------------------------------------
10                     1.6 (mean)             2.25       mouse    Bang &
                                                                  Northeved
                                                                  (1970)

8         0.5 - 1      2 - 4        2 - 4.5   2.25       man      Bang (1972)

6         0.9 - 1.56   6 - 14       5 - 11    2.25       man      Etienne et
                                                                  al. (1976)
                                                              
13        0.6 - 1.8    2 - 7.5      3 - 5.8   2.25       man      Takeuchi et
                                                                  al. (1977)

10        0.5 - 7.2    12 (mean)    6         2.0        man      Morohashi 
                                                                  & Iizuka 
                                                                  (1977)
------------------------------------------------------------------------------
a From:  Stewart & Stratmeyer (1982).
4.1.1.  Measurement of the total power of an ultrasound beam

    Measurement of total power is important for several reasons: 
(a) the total power of an ultrasound field impinging on an extended 
plane target can generally be measured more accurately than point 
or spatial quantities; (b) it is commonly used to characterize 
standard reference sources (such sources may be used in the 
calibration of detectors that measure point quantities, e.g., 
hydrophones); and (c) on measuring the total power for a defined 
field size, it is possible to calculate the mean intensity, usually 
referred to as spatial average intensity. 

    Ultrasound measurement procedures are discussed by various 
authors (O'Brien, 1978; Stewart, 1982).  Several methods are 
available for measuring total power, including radiation force, 
calorimetry, and acoustico-optical techniques, but the one which is 
usually favoured is radiation force.  This method, which can be 
used in the measurement of the total power output of ultrasound 
equipment, is based on the fact that the surface of a reflecting or 
absorbing target is performing a microscopic oscillation according 
to the continuity of particle velocity ( v) and partitioning of the 
momentum carried by the plane wave takes place at the surface. 
Consequently, the time average of the acoustic pressure at this 
non-stationary reference surface is non-zero.  The resulting steady 
pressure on the surface, multiplied by the exposure area, is called 
the radiation force.  The force produced is independant of frequency 
and is proportional to the total ultrasonic power impinging on the 
target.  The radiation force ( F) in newtons is given by: 

     F =  PD/ c                                           Equation 4.1

where  P is the incident acoustic power in watts,  c is the 
propagation velocity of the wave in m/s (in water  c = 1.5 x 103 
m/s at 30░C), and D is a dimensionless factor, determined by the 
type of interface encountered by the ultrasonic field and the 
direction in which the force produced by reflection or absorption 
is measured. 

    Values for D in Equation 4.1 are shown in Table 4.  The table 
has been modified from that of Hueter & Bolt (1955) to a more 
general situation (Stewart & Stratmeyer, 1982).  By knowing the 
type of interface a target presents to an ultrasonic field, and by 
measuring the magnitude of the force the total power in the 
acoustic field can be computed.  Typically, a flat, totally 
reflecting plate is used in radiation force devices.  For this 
situation, the only force produced by the reflected ultrasound is 
in a direction normal to the plate.  This force is given by 2 P/c 
cos theta, where theta is the angle between the normal to the 
reflecting surface and the ultrasound beam.  If the direction of 
measurement of force is not normal to the plate, only the component 
in the direction of measurement will be determined.  In this case, 
the force measured is  F = 2 P/c cos theta cos psi, where psi is the 
angle between the normal to the reflecting surface and the 
direction in which the force is to be measured. 

    If theta = psi, i.e., the ultrasound beam and the direction in
which the force is measured are the same, then  F = 2 P/c cos2psi,
which is the equation usually associated with these devices
(Hueter & Bolt, 1955).  For propagation in water, a collimated
beam of ultrasound exerts an apparent weight in the direction
of propagation equivalent to 0.136 cos2psi mg/mW or 0.067 mg/mW
for psi = 45░.

    The relationship in equation 4.1 applies for both cw and pulsed 
ultrasonic fields, provided that  P is taken as a time-averaged value. 
Because of inertia, the system cannot respond to the temporal 
variation of the pulsed ultrasound, unless the pulse repetition 
rate is extremely slow.  Many practical radiation force systems for 
measuring the output from both therapy and diagnostic sources have 
been described in the literature (Rooney, 1973; Stewart, 1975; 
Robinson, 1977; Brendel et al., 1978; Carson et al., 1978; Bindal & 
Kumar, 1979, 1980; Bindal et al., 1980; Carson, 1980; Shotton, 
1980). 

Table 4.  Values of the constant D for various physical situations
for a plane progressive ultrasound fielda
--------------------------------------------------------------------
Physical situation        Dx                Dy
--------------------------------------------------------------------
Perfect absorber,
normal incidenceb
r = 1                     1                 1 cos psi

Perfect reflector,
normal incidence
r = O or infinite         2                 2 cos psi

Perfect reflector,
ultrasound incident
at angle theta to
reflectorb
r = O or infinite         2 cos2theta       2 cos theta cos psi

Nonreflecting interface,
normal incidenceb
r = 1, c1=/=c2            1- c1/ c2           (1- c1/ c2) cos psi
                          For  c1 <  c2, force in direction of
                          propagation
                          For  c1 >  c2, force directed opposite 
                          to direction of propagation

Partially reflecting
interface, normal
incidence
 Z2=/= Z1,  c1=/= c2          2[(r-1)2/(r+1)2]  2[(r-1)2/(r+1)2] cos psi
--------------------------------------------------------------------
a   From: Hueter & Bolt (1955) and Stewart & Stratmeyer (1982).
b   r =  Z2/ Z1, the impedance ratio at an interface, where  Z = rho c.
x   where the direction of ultrasound propagations is the same as the
    direction in which the force is measured.
y   where the direction of ultrasound is not the same direction in 
    which the force is measured.
 c   = the velocity of ultrasound in the medium.
rho = the density of the medium.
theta = the angle between the normal to the reflecting surface and the
        incident ultrasound beam axis.
psi = the angle between the normal to the reflecting surface and the
      direction in which the force is measured.
=/= - not equal to

Note:

(1) When the direction of the incident ultrasound beam is the same 
as the direction in which the force is measured, then psi = theta 
and the value of D for a reflecting surface becomes 2 cos2theta; 
this is usually the case in practice. 
(2) When the direction in which the force is measured is the same 
as the direction of the normal to the reflecting surface, then psi 
= 0 and the value of D for a reflecting surface becomes 2 costheta. 

4.1.2.  Spatial and temporal measurements        
                                                                   
    Ideally, to measure the spatial and temporal characteristics of
ultrasound, a detector is needed that is small compared with the   
wavelength of the ultrasound field and has a response function     
(i.e., the quotient of the electric output signal and the acoustic 
imput signal) that is flat over the frequency of interest, combined
with high sensitivity, low noise, and a wide acceptance angle.     
Miniature piezoelectric hydrophones, though not ideal, are used    
extensively to determine the spatial distributions and temporal    
pressure waveforms and, when properly calibrated against an        
appropriate standard, can provide a satisfactory measurement       
method.  Wells (1977) describes various types of hydrophones that 
have been used.  Devices of this type respond to the instantaneous 
local value of the acoustic pressure in the field.  However, not 
all commercially available hydrophones are frequency independent in 
their sensitivity, and this presents a major problem.  The 
frequency responses of several hydrophones have been reported in 
the literature (Harris et al., 1977; Lewin, 1978, 1981a, b; Harris, 
1981). 

    The International Electrotechnical Commission (IEC, 1981) and 
the American Institute for Ultrasound in Medicine/National 
Electrical Manufacturers Association joint task group (AIUM-NEMA, 
1981) have both recommended the use of hydrophones for the 
measurement of spatial and temporal exposure parameters for 
diagnostic ultrasound equipment.  Comparison of the reciprocity 
technique for the calibration of ultrasonic hydrophones with that 
of planar scanning in a field of known acoustic power has shown 
that both methods yield consistent results (Gloerson et al., 1982). 
The choice of method depends on convenience and the interest and 
background of the user. 

    Most conventional probes have resonances in the frequency range 
of interest but distort the ultrasonic pulses being observed.  Only 
if the frequency characteristics of the probe are known, can 
appropriate corrections be made.  Another limitation in the use of 
hydrophones is their directional sensitivity, for which correction 
must be made.  The use of the piezoelectric polymer polyvinylidene 
fluoride as an ultrasonic hydrophone has been described (DeReggi et 
al., 1978, 1981; Wilson et al., 1979; Shotton et al., 1980; Harris, 
1981; Lewin, 1981b).  Compared with ceramic, this material has an 
acoustic impedance much closer to that of water and, because it is 
available in sheets that have thickness resonances greater than 20 
MHz, it promises to be useful as a broad-band, acoustically 
transparent receiver.  Hydrophones made with piezoelectric polymer 
are commercially available. 

4.2.  Measurement of Airborne Ultrasound Fields

    Both audible and ultrasonic fields are usually quantified in 
terms of sound pressure level (SPL), in decibels (dB): 

    SPL (dB) = 20 log10( p/pr)

where p is the acoustic pressure in free air.  The reference
pressure  pr is usually taken as  pr=20 micropascals (ÁPa),
which is equivalent to an acoustic intensity of  Ir=10-12W/m2.
This is approximately the lowest intensity of audible sound
perceived by human subjects at 1000 Hz.

    Since acoustic intensity is proportional to the square of 
acoustic pressure, the sound level can equally be expressed by: 

    SPL (dB) = 10 log ( I/Ir)

    Therefore, doubling the intensity  I increases the SPL by 3
dB, whereas doubling the pressure p increases the SPL by 6 dB.

    The actual determination of decibel levels at various positions 
in an airborne ultrasound field can be made with several 
commercially available systems (Michael et al., 1974; Herman & 
Powell, 1981).  These normally include a capacitor microphone 
sensing element having a flat frequency response within the range 
of interest, and signal processing circuitry.  Usually, this 
circuitry includes a set of one-third octave filters, so that the 
additive SPL within any particular one-third octave frequency range 
is indicated on the meter.  A spectrum of SPL as a function of 
frequency (to one-third octave resolution) can be obtained by 
"stepping through" the filter set.  When making SPL measurements, 
humidity and temperature conditions should be taken into account. 

    Rapid advances are being made in the development of ultrasound 
transducers for use in air, which have greatly improved resonance 
frequency and resolving capacity.  Commercially available 
transducers include electrostatic types, with linear frequency 
ranges up to a few hundred kHz (Frederiksen, 1977) and ceramic 
types, with quarter-wavelength matching to air and resonant 
frequencies up to 400 kHz (Kleinschmidt & Magori, 1981).  At these 
frequencies, the ultrasound wavelength in air is of the order of 
1 mm, which enables the construction of a whole line of new 
instrument systems using very narrow ultrasound beams (mm to cm) 
for remote measurements over distances ranging from millimetres to 
metres. 

    Applications using measurement of airborne ultrasound include: 
industrial remote measurements (size, location, speed etc.), 
anthropometrical measurements, and imaging of human beings 
(Lindstr÷m et al., 1982).  Measurements are performed using the 
ultrasound pulse-echo method, which means that many techniques used 
in diagnostic ultrasound can be transferred to high-frequency 
airborne ultrasound, i.e., different forms of real-time scanners 
(Lindstr÷m & Svedman, 1981). 

    Systems developed for measurement, control and imaging, and 
working with high-frequency (50-1000 kHz) airborne pulse-echo 
ultrasound, make use of narrow sound beams of high pulse intensity 
but low duty rate (Lindstr÷m et al., 1982).  Because of the short 
pulse duration, determination of the intensity level should be 

performed in a similar way to the procedure for diagnostic 
ultrasound; i.e., using spatial and temporal measurements to 
characterize the airborne ultrasound field. 

5.  SOURCES AND APPLICATIONS OF ULTRASOUND

    For many years, ultrasound was only used in the detection of 
submarines (Mason, 1976).  The device, first produced by Paul 
Langevin in 1917, was composed of a quartz crystal vibrating at 50 
kHz, propagating ultrasound into the water and detecting the 
reflected beam.  Ultrasound was first used therapeutically in the 
mid 1930s and for flaw detection between 1939 and 1945 (Firestone, 
1945; Desch et al., 1946). 

    Since the Second World War, considerable progress has been made 
in the development of new piezoelectric crystals, ferroelectric 
ceramics, and magnetrostrictive materials, and the applications of 
ultrasound have increased and diversified, particularly in recent 
years.  Fig. 6 includes examples of ultrasound devices used in 
medicine, industry, consumer products, and signal processing and 
testing, in relation to ultrasound frequency.  Besides the 
potential for occupational exposure to ultrasound in industrial and 
medical applications, members of the general population are now 
exposed to various consumer-oriented devices.  However, medical 
applications are the most rapidly increasing source of exposure. 
This section includes a brief review of domestic, industrial, 
commercial, and medical sources and applications of ultrasound. 

FIGURE 6

5.1.  Domestic Sources

    An ever increasing number of consumer-oriented devices emitting 
ultrasound are being manufactured.  Examples are garage door 
openers, television channel selectors, remote controls, burglar 
alarms, dog whistles, bird and rodent scarers, traffic control 
devices, and range-finders on cameras.  In general, low intensities 
and frequencies at the lower end of the ultrasound range (20-100 
kHz) are used in these applications and the ultrasound is usually 
propagated in air, so that the beam is rapidly attenuated over 
short distances. 

5.2.  Industrial and Commercial Sources            
                                                                   
    The industrial and commercial applications of ultrasound have  
been reviewed in a number of reports (Lemons & Quate, 1975;        
Lynnworth, 1975; Shoh, 1975; Jacke, 1979; Repacholi, 1981; Rooney, 
1981).  Generally, these applications can be divided into two      
categories (high- and low-power), depending on the power or        
intensity levels involved.  High-power applications usually rely   
on compound vibration-induced phenomena occurring in the object or 
material being irradiated.  These phenomena include cavitation and 
microstreaming in liquids, heating, and droplet formation at       
liquid/liquid and liquid/gas interfaces.  Some of the more common  
applications of high-power ultrasound are described in Table 5     
together with the ultrasound frequency and power or intensity range
used, where these variables are known.  The most practical frequency 
range for these applications is 20-60 kHz.  Most industrial ultra-
sound is produced using an electrostrictive or magnetostrictive 
transducer (Lynnworth, 1975), in which the dimensions of the 
elements change in response to an applied electric or magnetic field.
                                        
    Probably the oldest industrial application is cleaning by means 
of cavitation and microstreaming mechanisms.  Most cleaning tanks 
operate at intensities below 10 W/cm2, 2 W/cm2 being commonly used. 

    Plastic welding with ultrasound became popular in the mid 1960s 
and ultrasound is now used to assemble toys, appliances, and 
thermoplastic parts.  At frequencies above 20 kHz and intensities 
of more than 20 W/cm2, sufficient heat is produced to melt the 
plastic at the required locations.  The principal advantages of 
this method are speed, cleanliness, easy automation, and welding in 
normally inaccessible places.  An interesting application is the 
ultrasonic sewing machine.  Here woven or nonwoven fibres can be 
"sewn" together without thread. 

    Metal welding was introduced commercially in the late 1950s and 
is used in the semiconductor industry for welding or microbonding 
miniature conductors.  The process involves relatively low 
temperatures, usually below the melting point of the metal.  The 
welding depends on ultrasonic cleaning.  Ultrasonic shear causes 
mutual abrasion of the two surfaces so that exposed plasticized or 
metal surfaces can be joined under pressure to form a "solid-state" 
bond.  For this process, very high intensities are needed at the 
welding tip (of the order of 2000 W/cm2 at frequencies ranging from 
40 to 60 kHz). 


                                                                   
Table 5.  Industrial applications of high-power ultrasounda
--------------------------------------------------------------------------
Application      Description               Frequency  Power or intensity
                                           (kHz)      range
--------------------------------------------------------------------------
cleaning and     cavitating cleaning       18 - 100   usually below
degreasing       solution scrubs parts                10 W/cm2 but up
                 immersed in solution                 to 100 W power

soldering and    displacement of oxide     approx.    2 - 200 W/cm2
brazing          film to accomplish        30
                 bonding without flux

plastic welding  welding soft and          20 - 60    usually 20 - 30
                 rigid plastic                        W/cm2 but power
                                                      below 1000 W output

metal welding    welding similar and       10 - 60    up to 10 000
                 dissimilar metals                    W/cm2

machining        rotary machining,         usually 
                 impact grinding using     20
                 abrasive slurry,
                 vibration-assisted
                 drilling

extraction       extracting perfume,       approx.    about 500 W/cm2
                 juices, chemicals from    20
                 flowers, fruits, plants

atomization      fuel atomization to       20 -       up to 800 W
                 improve combustion        30 000
                 efficiency and reduce
                 pollution; also
                 dispersion of molten
                 metals

emulsification,  mixing and homogenizing   -          -
dispersion, and  liquids, slurries, and
homogenization   creams

defoaming and    separation of foam and    -          -
degassing        gas from liquid,
                 reducing gas and foam
                 content

foaming of       displacing air by foam    -          -
beverages        in bottles or containers
                 prior to capping

electroplating   increases plating rates   approx.    30 W
                 and produces denser,      27                     
                 more uniform deposit                           
--------------------------------------------------------------------------

Table 5.  (contd.)
---------------------------------------------------------------------------
Application      Description               Frequency  Power or intensity
                                           (kHz)      range
---------------------------------------------------------------------------
erosion          cavitation erosion        -          -
                 testing, deburring,
                 stripping

drying           drying heat-sensitive     -          -
                 powders, foodstuffs,
                 pharmaceuticals

cutting          cutting small holes in    approx.    about 150 W
                 ceramics, glass, and      20
                 semi-conductors
---------------------------------------------------------------------------
a From: Repacholi (1981).
    Ultrasound soldering, without fluxes, has also been carried out 
since the early 1950s.  Cavitation in the molten solder erodes the 
surface of metal oxides and exposes the clean metal to the solder. 
Simultaneous cleaning and tinning of the metal can be effected 
using ultrasonic intensities up to 100 W/cm2, at frequencies between 
20 and 50 kHz. 

    The machining of metals and ceramics can be carried out using 
an abrasive slurry between the vibrating tool and the work-piece. 
With a rotary machine and axial ultrasonic vibration, metals and 
other hard materials can be machined using diamond-impregnated core 
bits.  Ultrasonic cavitation accelerates the cutting action of the 
water-cooled core bits.  Usually, these devices operate at about 20 
kHz. 

    In high-power applications, the materials being worked are 
physically changed, whereas, in low-power applications, the 
ultrasound is used to examine rather than alter the materials.  
In many cases, low-power applications involve frequencies in the 
megahertz range (Table 6).  Applications include:  the 
determination of viscosity, transport properties, position, phase, 
composition, anisotropy and texture, grain size, stress and strain, 
elastic properties; the detection of bubbles, particles, and leaks; 
non-destructive testing; acoustic emission; imaging and holography; 
and counting by means of beam disruptions.  Many of the devices 
used in these applications have intrusive ultrasonic probes, but 
non-invasive pulsed and resonance techniques are also used. 


Table 6.  Low-power applications of ultrasound in industrya
-----------------------------------------------------------------------------
Application  Principle                                   Frequency
-----------------------------------------------------------------------------
Measurement 
of:
 flow        determining flow rates for gases, liquids,  1 - 10 MHz
             and solids - Doppler technique

 elastic     relating speed of sound to resonance        25 kHz - 300 MHz
 properties  modes of polarization

 temperature response to temperature dependence of       up to 30 MHz
             sound, speed, or attenuation

 thickness   timing round trip interval of pulse         2 - 10 MHz

 density,    resonant and non-resonant probe             up to 50 kHz
 porosity    transmission

 grain size  ultrasound attenuation                      few MHz
 of metals

 pressure    frequency of quartz crystal resonator       0.5 - 1 MHz
             changes with applied pressure

 level       attenuation of ultrasound beam or measure   around 100 kHz
             travel time (pulse echo technique)

Counting     beam interruptions counted                  40 kHz

Gas leaks    detection of ultrasonic "noise"             36 - 44 kHz

Flaw         observe discontinuities in reflected        25 kHz to
detection    beam                                        25 MHz (mW power)

Delay lines  transform electric signal into ultrasound   few MHz
             and back again after ultrasound has
             travelled a well-defined path

Burglar      ultrasound beamed into room and a certain   18 - 50 kHz
alarms       level of reflected beam is monitored; if    (mW powers)
             this level changes (with intruder) alarm
             sounds

Pest         frequency and intensity of ultrasound       18 - 50 kHz
control      bothersome to pests - inaudible to human    (mW powers)
             beings

Sonar        Doppler method determines presence and      5 - 50 kHz
             velocity of object                         

Acoustic     observe phase shift and attenuation of      100 - 3000 MHz
microscope   ultrasound beam by the specimen
-----------------------------------------------------------------------------
a Adapted from:  Lynnworth (1975).

                                                                  
5.2.1.  Airborne ultrasound exposure levels

    There is not a great deal of information concerning sound 
pressure levels produced by devices emitting airborne ultrasound. 
The US Bureau of Radiological Health has surveyed the output of 
several intrusion devices.  Peak sound pressure levels ranged from 
80 dB to 93 dB (centre frequency of one-third octave band) for 
those devices emitting at 20 kHz, 85 dB to 100 dB (half octave band 
levels) for those emitting at 25 kHz, and 75 dB to 90 dB for those 
at 16 kHz (Herman & Powell, 1981).  These levels were measured at 
positions where people were likely to remain for a reasonable 
length of time.  In some cases, levels were as high as 140 dB at 
the surface of the radiating transducer. 

    Michael et al. (1974) monitored the output of several devices, 
including ultrasonic cleaners.  Sound pressure levels measured near 
some ultrasonic cleaners surveyed were as high as 117 dB (20 kHz 
centre frequency of one-third octave band).  Ultrasonic energy 
emitted into air from other ultrasonic cleaners of 300 W and 150 W, 
measured at 1 m from the cleaners, was 127 dB and 113 dB (28 kHz 
centre frequency one-third octave band), respectively (Ide & Ohira, 
1975). Similar results were obtained by Crabtree & Forshaw (1977) 
and Herman & Powell (1981). 

    A dental drill emitted approximately 80 dB (one-third octave 
band sound from 16 kHz to 100 kHz), and an insect repeller radiated 
61 dB (16 kHz centre frequency, one-third octave band).  More 
detailed information on emissions of airborne ultrasound from 
various devices has been compiled by Michael et al. (1974). 

5.3.  Medical Applications

    The use of ultrasound in medicine has grown rapidly since the 
early 1970s, especially in the diagnostic field.  This is the 
result of the availability of good imaging equipment, the 
development of many new applications, and the increasingly accurate 
diagnoses that can be made using new techniques.  In addition, 
there is a common contention that no risks are associated with 
ultrasound exposure. 

    In the past, imaging equipment has been generally confined to 
hospital centres, but today, with the marketing of imaging and 
Doppler devices at relatively low cost, it is common for 
obstetricians to have the equipment in their private clinics.  In 
many countries, more than 50% of women are exposed to ultrasound 
during pregnancy and, in some clinics, all women are examined one 
or more times. 

5.3.1.  Diagnosis

    Ultrasound was introduced into diagnostic medicine in the mid 
1950s and its use has increased at such a rate that "with expanding 
services in ultrasound diagnosis, the frequency of human exposure 
is increasing with the potential that essentially the entire 
population of some countries may be exposed" (IRPA, 1977).  The 

National Center for Devices and Radiological Health (US Department 
of Health and Human Services) estimates that the availability of 
equipment will be such that every pregnant woman in the USA could 
undergo at least one ultrasound examination of the fetus (Stewart & 
Stratmeyer, 1982). 

    Most medical diagnostic applications of ultrasound are in the 
frequency range of 1-10 MHz, except for ophthalmological 
examinations, which may be performed at frequencies up to 30 MHz. 
These examinations are carried out using either pulsed or cw 
irradiation. 

    Added to the growth in sales of equipment and the increasing 
numbers of people being exposed to ultrasound is the fact that new 
diagnostic techniques are constantly being developed.  With 
sophisticated imaging devices, ultrasound imaging technology is 
making great advances.  Since the development of computerized axial 
tomography (Hounsfield, 1973) using X-rays, analogous images have 
been obtained using ultrasound.  Ultrasonic spectroscopy, time-
delay spectrometry, and holographic techniques all offer new 
potential for this expanding imaging modality. 

    Reviews of the diagnostic applications of ultrasound include 
those by Lyons (1982), Repacholi (1981), and Stephenson & Weaver 
(1981).  Some of the areas of the body commonly investigated and 
the types of examination performed are listed in Table 7.  From 
this compilation of diagnostic procedures, it can be seen that 
certain areas of the body are efficiently examined using 
ultrasound.  Areas better examined with other imaging modalities 
are those containing large amounts of gas (e.g., lungs). 
                                                                             
Table 7.  Some applications of diagnostic ultrasounda                            
---------------------------------------------------------------------------------
Part of interest       Measurement made                                          
                                                                                 
1. Head               echoencephalography (head scan and brain scan) for        
                        midline position determination and ventricular size      
   brain               neonatal brain tomographic scans,                         
                        hydrocephalus evaluation                                 
                                                                                 
2. Eyes and orbit      ophthalmic echography (eye scan) for ultrasonic           
                        biometry, foreign body localization, mass                
                        evaluation, retinal detachment                           
                                                                                 
3. Neck                arterial flow studies, plaque evaluation, carotid artery  
   thyroid             thyroid echography (thyroid scan) for mass evaluation     
                                                                                 
4. Chest                                                                         
   heart               echocardiography (heart scan) for pericardial             
                        effusion, valve investigation, wall evaluation           
                        (motion, thickness), chamber size and function,          
                        tumour detection, intra-cardiac blood flow               
   pleural space       effusion localization                                     
   breast              breast echography (breast scan) for mass evaluation       
---------------------------------------------------------------------------------

Table 7.  (contd.)
---------------------------------------------------------------------------------
5. Abdomen                                                                       
   liver                                                                         
   kidneys             evaluation of size, parenchyma,                           
   spleen               and associated masses                                    
   pancreas                                                                      
   gallbladder         stone detection                                           
   biliary ducts       evaluation of size                                        
   aorta               aneurysmal dilatation                                     
   peritoneal space    ascites and abscess detection                             
                                                                                 
6. Pelvis                                                                        
   uterus (pregnant)   evaluation of fetus, gestational sac,                     
                        estimation of fetal age, diagnosis of multiple           
                        pregnancy, placental localization, amniotic              
                        cavity, fetal heart monitoring, fetal growth             
                        rate, molar pregnancy, ectopic pregnancy, fetal          
                        breathing, congenital anomalies                          
   uterus (non-        evaluate nature and size of masses                        
    pregnant)                                                                     
   ovaries             following Graafian follicle development for               
                        ovulation timing                                         
   bladder             tumour assessment                                         
   prostate            tumour detection                                          
                                                                                 
7. Extremities                                                                   
   arteries and veins  vascular studies, peripheral flow                         
                                                                                 
8. Ultrasonic          Ultrasonic guidance for amniocentesis, needle             
   guidance             biopsy, thoracentesis or cyst location, placement        
   procedures           of ionizing radiation therapy fields                     
---------------------------------------------------------------------------------
a From:  Lyons (1982).                                                            

5.3.1.1.  Exposure levels from diagnostic ultrasound equipment

    While, at present, most manufacturers fail to provide 
information on exposure levels with their equipment, ultrasonic 
intensity levels and total power output measurements from 
commercial diagnostic instruments have been reported by several 
investigators (Hill, 1971; Rooney, 1973; Carson et al., 1978; 
Farmery & Whittingham, 1978; Kossoff, 1978; Stewart, 1979; Zweifel, 
1979).  These results should be interpreted with care, since 
different criteria and techniques were employed to obtain the data. 
Output levels from a limited number of different types of 
diagnostic devices, reported by various investigators, are 
summarized in Table 8. 

    The levels of output from cw peripheral vascular Doppler units 
are high, compared with those from obstetric Doppler units.  This  
is due, in part, to the sensitivity that is required to detect the 
small signals received from flowing blood.  The SATA intensity     
output levels at the face of the transducer for single element     

pulse echo A and B mode imaging units are in the low mW/cm2 range. 
The intensities at the transducer face are much lower than the     
intensities measured at the focal distance for units using focusing
transducers.  Though the reported SATA intensities may be in the   
mW/cm2 range (Table 8), the SPTP intensities can sometimes be in   
the hundreds of W/cm2 range.                                       

    In the case of automatic scanners equipped with a mechanical   
sector scan or a multi-element transducer providing a linear or    
sector scan motion of the ultrasound beam, the time pattern of 
the sound field at a point of interest is characterized by the 
pulse   shape and pulse duration (typically around 1 Ás), the pulse        
repetition frequency (typically a few kHz) and the frame repetition 
frequency (typically 10-50 Hz).  When the beam is scanned over the 
point of interest, a short sequence of pulses, the number of which 
is given by the ratio of the beam width to the beam shift between  
subsequent pulses (typically 2-5 pulses) is recorded at this point. 
While SPTP intensities of the order of 10 W/cm2 occur at the       
pressure maxima of these few pulses, the SPTA intensity, when      
averaged over the short sequence of pulses, is of the order of 1-10 
mW/cm2.  After the short pulse group, the ultrasound intensity at  
the point of interest remains at a very low level while the beam is 
scanned to other positions.  Thus the SPTA intensity, when averaged 
over the total period of one frame, is proportional to the ratio of 
the number of pulses in the short sequence to the total number of  
pulses per frame.  This ratio may vary from 0.01 to 0.05, so that  
SPTA intensities of 0.01-0.5 mW/cm2 result, when averaged over the 
total frame time.                                                  

5.3.2.  Therapy
                                                                    
    Ultrasound therapy usually involves the application of a hand-  
held ultrasound transducer to the injured area of a patient, and    
treatment with either a cw or pulsed beam. Intensities employed in  
physiotherapy normally range from about 100 mW/cm2 to 3 W/cm2.  The 
transducer head is generally moved over the area of injury to obtain
as uniform a treatment distribution as possible.                    

     Lehmann et al. (1974, 1978) pointed out that the main 
therapeutic value of ultrasound was related to its selectivity of 
absorption.  In soft tissue, this absorption may be directly related 
to the protein content of the tissue (Piersol et al., 1952; Bamber 
et al., 1981). Lehmann et al. (1974) also claimed that the benefit 
of ultrasound as a therapeutic agent was that it heated selectively 
the areas that required heating, including superficial bone, scar 
tissue within soft tissue, tendons and tendon sheaths, etc. 
Furthermore, they claimed that ultrasound might accelerate the 
diffusion process across biological membranes, implying an 
increased rate of healing.  There may also be low-intensity, 
ultrasound-induced, non-thermal effects, which may be important in 
certain physiotherapeutic applications, such as the breakdown of 
fibrous adhesions at the site of a surgical incision (Wells, 1977; 
Coakley, 1978; ter Haar et al., 1980). 


Table 8.  Range of output intensities found in beams produced by medical ultrasonic 
equipmenta
---------------------------------------------------------------------------------------------
Type of equipment         Spatial average,   Spatial peak      Spatial peak   Spatial peak
                          temporal average   temporal average  pulse average  temporal peak
                          (SATA)             (SPTA)            (SPPA)         (SPTP)
                          intensity on the   intensity         intensity      intensity
                          radiating surface                                             
---------------------------------------------------------------------------------------------
static pulse echo                                                            
scanners A-mode           0.2-20 mW/cm2      0.6-125 mW/cm2    0.1-160 W/cm2  0.4-1000 W/cm2
                                                                             
automatic sector                                                             
scanners (phased                                                             
arrays and wobblers)      0.5-60 mW/cm2      2-200 mW/cm2      0.3-100 W/cm2  4-120 W/cm2
                                                                             
sequenced linear arrays   0.06-10 mW/cm2     0.1-12 mW/cm2     0.3-100 W/cm2  4-120 W/cm2
                                                                             
pulsed Doppler,                                                              
primarily for cardiac                                                        
work                      3-32 mW/cm2        20-290 mW/cm2     1-14 W/cm2     2-28 W/cm2
                                                                             
Doppler instruments,                                                         
primarily for obstetric                                                      
applications              0.26-25 mW/cm2     0.75-75 mW/cm2   
                                                                             
continuous wave Doppler,                                                     
primarily for peripheral                                                     
vascular investigations   10-400 mW/cm2      20-800 mW/cm2    
                                                                             
therapy continuous wave   up to 4 W/cm2      0-16 W/cm2       
                                                                             
therapy, gated mode       up to 1 W/cm2      0-4 W/cm2        
---------------------------------------------------------------------------------------------
a Intensity data were obtained from published values in the literature
  (Rooney, 1973; Etienne et al., 1976; Carson et al., 1978; O'Brien,
  1978; Nyborg, 1979; Stewart, 1979; AIUM-NEMA, 1981; Hill & ter Haar,
  1981; Stewart & Stratmeyer, 1982).  Measurements were made with
  transducers immersed in water.

                                                          
    The stimulatory effect of ultrasound in healing ulcers in human 
subjects has been reported by various investigators (Dyson et al., 
1976; Goralcuk & Kosik, 1976).  Dyson et al., (1976) suggested that 
nonthermal mechanisms might be involved in the beneficial therapeutic 
action of ultrasound on tissues. 

    It is, however, very difficult to assess the benefits from 
ultrasound therapy, as Roman (1960) found.  Of 100 patients treated 
or sham-irradiated for lower back pains, bursitis of the shoulder, 
and myalgia, 60% receiving ultrasound were categorized as normal, 
but 72% of the shams were in the same category.  Many more well-
controlled studies ought to be conducted to identify optimal 
exposure conditions and to eliminate ineffective treatments. 

5.3.2.1.  Exposure levels from therapeutic ultrasound equipment

    Ultrasonic therapy units are usually equipped with an indicator 
of the total output power (either a meter or calibrated dial), a 
timer, and a power output adjustment.  They usually register total 
output power in watts (W) and intensity in W/cm2, which is the 
power divided by the effective radiating area of the transducer.  
Some ultrasound units can be operated in either cw or gated mode 
(Fig. 2).  In the gated mode, most units operate at a gate 
repetition rate from about 8 Hz to 120 Hz with a gate width of up 
to 12 ms.  Gated mode therapy units are normally calibrated in terms 
of the cycle average intensity ( Ia) (Appendix I). 

    In cw operation, the ultrasonic power and spatial average 
intensity can be adjusted up to about 20 watts and 4.0 W/cm2, 
respectively (Repacholi & Benwell, 1979).  In gated mode, the peak 
power and temporal peak spatial average intensity in one unit could 
be adjusted up to approximately 80 watts and 8.0 W/cm2, respectively 
(Stewart et al., 1982). 

    Because beam divergence is a function of applicator size for a 
given ultrasonic frequency, therapy transducers with beam areas of 
less than 5 cm2 have been stated by some to be unacceptable (Lehmann, 
1965a,b).  In addition, with a small beam it may be difficult to 
treat a large area on an individual.  On the other hand, if the 
radiating area of the applicator is too large, it may be difficult 
to maintain contact with curved surfaces of the body during 
treatment.  The effective radiating area of therapy applicators 
generally ranges between 1 and 10 cm2. 

5.3.3.  Surgical applications

    Ultrasound has been used in vestibular surgery for the 
treatment of MÚniŔre's disease.  The treatment involves ultrasound 
exposure of the vestibular end organ to SPTA intensities of 10-22 
W/cm2 from a specially designed ultrasonic probe (James, 1963; 
Kossoff & Khan, 1966; Sorensen & Andersen, 1976). 

    Kelman (1967) first described the use of a phacoemulsification 
and aspiration technique for the removal of cataracts  in situ.  The 
low-frequency probe (phacoemulsifier) is inserted into the lens of 

the eye to break up the cataract, then the broken pieces are sucked 
out through a hollow tube.  This technique has been refined and used 
successfully (Emery, 1974; Emery et al., 1974; Emery & Paton, 1974; 
Girard, 1974). 

    Other surgical procedures in which ultrasound has been used 
include:  cleaning of obstructed blood vessels and ureters, and 
fragmenting kidney-stones (Davies et al., 1974, 1977; Stumpff et 
al., 1975; Finkler & Hausler, 1976; Yeas & Barnes, 1970), 
neurosurgery (Arslan et al., 1973), and cutting and welding tissues 
(Goliamina, 1974; Hodgson et al., 1979; Williams & Hodgson, 1979). 

    Non-surgical destruction of kidney-stones can be performed by 
repeated application of acoustic shock-waves (Chaussy et al., 
1980).  The patient is treated lying in a water-bath, where high-
intensity ultrasound pulses of microsecond duration, are generated 
by electrical discharges from a spark-gap, placed in one focus of a 
concentrating ellipsoidal ultrasound mirror system.  Exact 
positioning of the patient is performed under X-ray guidance.  This 
enables continuous visualization of the gradual disintegration of 
the stone during the treatment. 

5.3.4.  Other medical applications

    Ultrasound has been used to atomize liquids, in order 
to produce aerosols that can maintain a humid atmosphere in a 
ventilating assistor (Miller et al., 1968).  Boucher & Krueter 
(1968) described several ultrasonic nebulizers which are available 
commercially.  These devices operate at 1-1.4 MHz and produce 
aerosols with particle diameters of between 1 and 1.4 Ám. 

    Methods in which gas bubbles are detected by increases in 
ultrasound attenuation due to the bubbles in tissue have been 
described by Manley (1969).  In other methods, the fact that gas 
bubbles circulating  in vivo give rise to characteristic changes in 
the output from a cw Doppler device has been used to detect these 
bubbles (Evans & Walder, 1970).  Ultrasound frequencies ranging 
from 1 to 3 MHz and intensities of a few mW/cm2 are employed in 
these procedures.  Ultrasonic pulse-echo imaging has also been used 
to study decompression-induced gas bubbles  in vivo (Daniels et al., 
1979). 

    The application of ultrasound to the acupuncture meridian 
system has been reported by Khoe (1977).  Output powers of 0.25-1 W 
for 0.5-2 min are used at each acupuncture point.  Presumably, the 
frequency of the transducer is somewhere in the range of 0.8-3 MHz, 
though this is not specifically mentioned by the author.  This 
technique was claimed to be effective for a variety of viral, 
bacterial, and fungal diseases; allergic, gastrointestinal, 
gynaecological, and musculo-skeletal disorders; and cardiovascular 
diseases. 

    Kremkau (1979) has completed a review of events leading up to 
the relatively new use of ultrasound for cancer therapy.  Ultrasound 
can produce hyperthermia in surface and deep-seated tissue volumes 
(Lele, 1967; Palzer & Heidelburger, 1973) (section 6.4.6.5). 

5.3.5.  Dentistry

    The ultrasonic drill was developed in the early 1960s but never 
really gained acceptance in dentistry because of the introduction 
of the high-speed rotary drill.  However, the number of other 
applications of ultrasound in dentistry has been steadily growing 
(Balamuth, 1967).  These include cleaning and calculus removal, 
gingivectomy, root canal reaming, orthodontic filling, amalgam 
packing, and gold-foil manipulation.  Conventional techniques for 
these tasks are fairly satisfactory, but there is no doubt that the 
silence and ease of the ultrasonic methods relieves the patient of 
some of the stress associated with dental treatment.  Frost (1977) 
estimated that in the USA there may be as many as 100 000 
ultrasonic units in use in dental offices for scaling teeth and 
peridontal care. 

    It appears that long-term studies on the biological effects of 
ultrasound devices in dentistry have not been reported in the 
literature.  The extent to which these devices are hazardous 
depends largely on how they are used.  While investigators tend to 
attribute most of the bioeffects to heating, the cavitation 
associated with the water coolant spray cannot be ignored, 
especially subgingivally.  When used improperly, ultrasound dental 
devices are apparently more likely to be hazardous or ineffective 
than conventional techniques.  Most of the commonly used dental 
devices operate in the frequency range of 20-40 kHz. 

6.  EFFECTS OF ULTRASOUND ON BIOLOGICAL SYSTEMS

6.1.  Introduction

    The studies reviewed in this section have been arranged 
according to the complexity of the biological systems under study, 
i.e., from macromolecules to complete multicellular organisms. 
Caution must be exercised, when interpreting the results of many of 
the studies involving macromolecules and cells in suspension.  The 
acoustic mechanism(s) of interaction predominantly responsible for 
effects in these systems may not necessarily be the same as those 
responsible for effects in intact tissue or organisms.  However, 
because of the problems inherent in using intact animals to search 
for unpredicted effects, macromolecular and cellular studies may 
provide valuable information concerning end-points that might 
reasonably be examined in higher level organisms. 

    The data concerning biological effects are incomplete, because 
few biological structures have been subjected to systematic 
examination for effects from ultrasound.  Estimates of ultrasound 
field variables in living systems still suffer from a lack of 
accepted methods of measurement, and often from inadequately stated 
experimental conditions.  In many  in vitro experiments, cell 
suspensions have been in contact with foreign surfaces (e.g., test-
tubes, culture dishes, plastic) during ultrasound exposure.  The 
complex acoustic fields reflected from these surfaces frequently 
make it difficult to determine the cell exposure levels and to 
compare the results with those of studies conducted using different 
experimental arrangements. 

    Unfortunately, the SATA intensity has been determined in 
different ways in many bioeffects reports.  In some studies, it has 
been determined as indicated in Appendix II.  In others, the total 
power of the beam has been determined and divided by the area of 
the transducer face.  This variation in the methods of determination 
of SATA intensity introduces difficulties when comparing the 
results of different laboratories. 

    The evidence that is presented should be considered as 
inconclusive, in most cases, until confirmed by independent 
laboratories. 

6.2.  Biological Molecules

    Extensive work has been carried out on the action of ultrasound 
on chemical systems and, in particular, on large molecules of 
biological interest (El'piner, 1964).  The effects at this level 
are broadly of three kinds (Edmonds, 1972):  (a) passive absorption 
of the (coherent) ultrasound energy; (b) mechanical degradation of 
large molecules; and (c) chemical effects, apparently attributable 
to the action of cavitation in releasing chemically active "free 
radical" species in irradiated solutions. 

    It has been shown that the absorption properties of blood are 
mainly determined by, and are directly proportional to, its protein 
content (Kremkau & Carstensen, 1972; O'Brien & Dunn, 1972). 

Furthermore, since the frequency dependence of ultrasound 
absorption by whole and homogenized liver tissue is very similar, 
it has been concluded that approximately two-thirds of the 
absorption occurs at the macromolecular level, with one-third due 
to the tissue structure (O'Brien & Dunn, 1972).  For a more 
extensive coverage of the literature in this area, the reader is 
referred to reviews by Repacholi (1981) and Stewart & Stratmeyer 
(1982). 

    There have been a number of studies on the effects of 
ultrasound on solutions of purified DNA. Hill et al. (1969) found 
that a 3-min exposure of calf thymus DNA to cw 1 MHz ultrasound at 
400 mW/cm2 resulted in DNA degradation.  Similarly, Galperin-
Lemaitre et al. (1975) reported that exposing calf thymus DNA to 1 
MHz ultrasound, at 200 mW/cm2, resulted in DNA degradation.  The 
DNA strand breakage was thought to be due to hydrodynamic shear 
stress generated by acoustic cavitational activity. 

    In summary, though solutions of macromolecules such as proteins 
and nucleic acids are capable of absorbing ultrasound in the 
megahertz frequency range, damage has usually been reported only as 
a result of cavitation.  However, it is not clear if these data can 
be extrapolated to the  in vivo situation, since the structure of 
DNA in solution bears little resemblance to its structure  in vivo. 

6.3.  Cells

    Studies aimed at elucidating the mechanisms of action of a 
particular agent may be more readily performed and analysed using 
cell suspensions than the whole animal, because of the absence of 
numerous uncontrollable biological variables.  Effects observed in 
mammalian cells, after ultrasound exposure, include:  modification 
of macromolecular synthetic pathways and cellular ultrastructure; 
cell lysis, cellular inactivation, and altered growth properties; 
and chromosomal changes.  Current information concerning such 
effects will be discussed in this section with the exception of 
chromosomal changes, which will be discussed in section 6.4.4. 

6.3.1.  Effects on macromolecular synthesis and ultrastructure

     Alterations in the rates of protein and DNA synthesis have 
been reported to occur in cells grown in tissue culture, when 
exposed to ultrasound. 

6.3.1.1.  Protein synthesis

    Stimulation of the rate of protein synthesis was observed 4 
days after exposure of human fibroblasts for 5 min to cw 3 MHz 
ultrasound at intensities of 0.5-2.0 W/cm2 (Harvey et al., 1975). 
Continuous wave exposure at 0.5 W/cm2 caused total protein 
synthesis in fibroblasts to increase by 20%, while exposure to 
pulsed ultrasound (pulse duration 2 ms; duty factor, 0.2) at the 
same average intensity resulted in a 30% increase compared with 
control values (Harvey et al., 1975; Webster et al., 1978).  The 
stimulation, which appeared to be inversely related to the 

ultrasound frequency in the range 1-5 MHz, did not occur when the 
cells were pretreated with cortisol.  The authors suggested that 
the increased protein synthesis observed was due to damage to the 
lysosomal and plasma membranes (possibly by a cavitational 
mechanism of action), since no ultrastructural changes occurred if 
the cells were exposed at elevated pressures. 

    Belewa-Staikowa & Kraschkowa (1967) observed an increase in 
protein synthesis in hepatic, renal, and myocardial tissue treated 
with a single, 5-min exposure to a therapy transducer at intensities 
of both 0.2 and 0.6 W/cm2.  However, protein synthesis was retarded 
at 1 W/cm2.  A similar effect was found by Repacholi (1982) in that 
stimulation of protein synthesis occurred in human lymphocytes at 
low cw therapeutic intensities (870 kHz, 1.1 W/cm2, 30 min), and 
retardation at higher intensities (3-4 W/cm2). 

6.3.1.2.  DNA

    Increased DNA synthesis  in vitro was observed 1, 2, and 3 days 
after exposure of excised neonatal mouse tibiae to cw 1 MHz ultra-
sound at 1.8 W/cm2 (Elmer & Fleischer, 1974).  However, no 
statistically significant differences were observed in either 
protein accumulation or in bone elongation compared with the 
controls. 

    Levels of (3H) thymidine and (3H) deoxyuridine incorporated 
into DNA decreased to 54% and 42% of control values, respectively, 
following exposure of mouse leukaemia 1210 cells to 2.22 MHz 
ultrasound for 10 min, at a mean spatial intensity of 10 W/cm2 
(Kaufman & Kremkau, 1978).  The authors found that ultrasound caused 
reversible injury in the cell, which was not readily reversed in 
the presence of cytotoxic drugs, and that this resulted in a 
significant decrease in the lethal potential of the leukaemia 
cells.  A significant immediate inhibition in the incorporation of 
(3H) thymidine was also found by Repacholi et al. (1979) and 
Repacholi (1982), when human blood lymphocytes were exposed  in 
 vitro to therapeutic ultrasound (cw near-field, 870 kHz, 4 W/cm2, 
for 30 min).  The uptake of the radioactive precursors returned to 
control levels, 2-3 days after exposure (Repacholi, 1981). 

    Fung et al. (1978) exposed activated human lymphocytes to cw 
ultrasound for 0-30 min using a commercial fetal Doppler unit.  The 
uptake of (3H) thymidine over an 18-h period, 1 day after ultra-
sound exposure, was found to be biphasic.  There were lymphocytes 
that showed significant stimulation in uptake at short exposure 
times (3-12-min exposure) with a return to control values at longer 
exposure times (15-30-min exposure), and lymphocytes that did not 
exhibit any stimulatory effect at short exposure times, but showed 
a significant reduction in uptake with 12- and 30-min exposures. 

    In a study by Liebeskind et al. (1979a), exposure of 
synchronized HeLa cells in culture to pulsed 2.5 MHz ultrasound at 
a SATA intensity of 17 mW/cm2 (35.4 W/cm2 SPTP intensity) induced 
unscheduled, non-S-phase (repair) DNA synthesis.  This result 
suggested that the DNA had been damaged by the ultrasonic exposure. 

A similar effect was reported by Repacholi & Kaplan (1980), who 
found non-S-phase unscheduled DNA synthesis in human peripheral 
blood lymphocytes exposed to cw near-field, 870 kHz ultrasound at 4 
W/cm2 for 30 min. 

    In another study, Liebeskind et al. (1979b) found a small but 
significant increase in the frequency of sister chromatid exchanges 
(SCE), following a 30-min exposure of normal human lymphocytes to 
pulsed diagnostic ultrasound of frequency 2.0 MHz, at 2.7 and 5.0 
mW/cm2 (SATA intensity).  Results consistent with these were 
reported by Haupt et al. (1981) who used a commercial real time 
scanner, having a pulse repetition frequency of 2420 Hz at 3.5 MHz, 
pulse duration of 0.89 Ás, estimated SPTP intensity of 2 W/cm2, and 
SPTA intensity of 0.02 mW/cm2 for 7.5-90 min.  However, Morris et al. 
(1978), who used cw 1 MHz ultrasound exposures at intensities of 
9.1, 15.3, 27, and 36 W/cm2 did not find an increase in SCEs.  The 
time of exposure was also different in that unstimulated stationary 
phase (Go) lymphocytes were exposed before both divisions, whereas, 
in the studies by Liebeskind et al. and Haupt et al., stimulated 
lymphocytes were exposed after the first division, but before the 
second.  Thus the experimental conditions were completely different; 
the cells used by Morris et al. (1978) were in a less sensitive 
state and therefore the results are not comparable.  Wegner et al. 
(1980), who exposed Chinese hamster ovary cells to cw 2.2 MHz 
ultrasound at 10 mW/cm2 for 30 and 90 min using a fetal Doppler 
unit, also did not observe any increase in SCE.  These data raise 
questions about the possible effectiveness of pulsed diagnostic 
ultrasound compared with cw exposures in causing SCE. 

    The significance of SCE in relation to biological hazard is not 
understood, though the phenomenon is generally held to be 
undesirable.  For some other types of insults, sister chromatid 
assay has been suggested to be a sensitive measure of genetic 
damage, because the frequency of exchanges increases after exposure 
of cells to known mutagens and carcinogens (Stetka & Wolff, 1977). 
The SCE method has been advocated as a direct test of mutagenic or 
carcinogenic agents (Latt & Schreck, 1980; Shiraishi & Sandberg, 
1980). 

6.3.1.3.  Cell membrane

    Ultrasonically-induced functional alterations in the plasma 
membrane have been reported by a number of investigators.  These 
alterations include increased permeability, decreased active 
transport, decreased non-mediated transport, and decreased 
electrophoretic mobility.  A 5% decrease in the non-mediated 
transport of leucine in avian erythrocytes following a 30-min, 
1 MHz ultrasound exposure at an intensity of 0.6 W/cm2 was reported 
by Bundy et al. (1978).  However, no change was observed in the 
active transport of (3H) thymidine in human lymphocytes exposed to 
cw 870 kHz ultrasound at intensities up to 4 W/cm2, for 30 min 
(Repacholi, 1982). 

    A reduction in the electrophoretic mobility of Ehrlich ascites 
tumour cells observed by Repacholi (1970) and Repacholi et al. 
(1971) was directly proportional to the square root of the ultra-
sonic frequency used in the range of 0.5-3.2 MHz (Taylor & Newman, 
1972).  This reduction in mobility was reported to be independent 
of the pulse length over the range of 20 Ás-10 ms (peak intensity 
was 10 W/cm2; duty factor, 0.1, exposure time, 5 min).  The change 
in mobility was presumably a result of alteration of the surface 
charge of the cells. This effect was also reported by Joshi et al. 
(1973) and later reported to be reversible and non-lethal by Hill 
& ter Haar (1981). 

    A mechanical stress mechanism of action was suggested to be the 
cause of an increase in the permeability of human erythrocyte 
membranes to potassium ions, observed following ultrasound exposure 
 in vitro for 5-30 min (1 MHz, 0.5-3.0 W/cm2) (Lota & Darling, 1955). 
A decrease in potassium content was reported to occur following 
sonication of rat thymocytes for 40 min, using an ultrasonic 
therapy unit operated at 3 MHz and 2 W/cm2 (Chapman et al., 1980). 
These changes appeared to be a result of both a decreased influx and 
an increased efflux of potassium. 

    Changes in the concentrations of membrane-associated cAMP and 
cGMP have profound effects on a wide variety of cellular processes. 
However, no alterations in the amount of cAMP and cGMP could be 
detected following exposure of human amniotic cells or mouse 
peritoneal cells to cw 1 MHz ultrasound at 1 W/cm2 for 33 min 
(Glick et al., 1979). 

    Siegel et al. (1979) reported that dispersed cultured human 
cells seeded in plastic Petri dishes showed significantly reduced 
cellular attachment after 0.5 min of exposure to a pulsed, 2.25 MHz 
clinical diagnostic ultrasound source (approximate SATA intensity, 
10 mW/cm2).  The authors suggested that, if cellular attachment 
were to be altered  in vivo, it could affect implantation, 
morphogenesis, and development.  These results may be related to 
findings described by Liebeskind et al. (1981a) on the spectacular 
morphological changes in cell surface characteristics observed 
after pulsed diagnostic ultrasound exposure.  Mouse 3T3 cells 
examined for up to 37 days after a single exposure demonstrated 
abnormally large numbers of microvilli and cell projections. 
Thirty-seven days represents 50 generations for this cell line and 
suggests that the altered cell surface characteristics were a 
result of a hereditary change.  However, Mummery (1978) did not 
observe these changes following exposure of fibroblasts to either 
pulsed or cw therapeutic ultrasound. 

    Martins (1971) reported that scanning electron micrographs of 
M3-1 cells exposed to 1 MHz ultrasound at 1.0 and 0.25 W/cm2 showed 
a characteristic bumpy outer surface, compared with the smooth 
outer surface of unexposed cells. 

    The motility  in vitro of sparse populations of human embryo 
lung fibroblasts was found to increase after exposure to 3 MHz 
ultrasound at SPTP intensities of 0.5-2.0 W/cm2, pulsed 2 ms on, 

8 ms off for 20 min.  This was the result of an increase in 
directionality rather than an increase in mean speed (Mummery, 
1978).  The author suggested that this effect could be implicated 
in the beneficial therapeutic actions of ultrasound on wound 
healing. 

    An increase in the calcium ion content of human embryonic lung 
fibroblasts resulted from  in vitro exposure to 3 MHz ultrasound, at 
SPTP intensities of 2 and 4 W/cm2 pulsed 2 ms on, 8 ms off, for 20 
min.  The effect was still observed, when the cells were washed with 
ethylene diamine tetracetic acid (EDTA) after treatment, but was 
suppressed by doubling the ambient pressure during sonication.  This 
strongly implicates acoustic cavitation as the dominant mechanism 
(Mummery, 1978). 

    In summary, there are several reports indicating that 
diagnostic levels of pulsed ultrasound can cause structural and 
functional changes in cell surface characteristics.  Because of the 
importance of the cell surface in immune determination, receptor 
topography carrier systems, and cell-cell recognition, these 
changes could have quite important ramifications  in vivo.  However, 
the interpretation of the results of cell culture experiments in 
terms of an  in vivo situation is speculative, because of the 
difficulty in bridging the gap between experimental  in vitro work 
and biological effects that occur in the patient. 

6.3.1.4.  Intracellular ultrastructural changes                   
                                                                  
    Numerous reports have appeared describing ultrastructural     
damage to cells exposed to ultrasound.  Rat bone-marrow cells in  
suspension, irradiated with 0.8 MHz ultrasound for 1 min at 1.5   
W/cm2, exhibited gross damage, when examined by electronmicroscopy
(Dunn & Coakley, 1972).                                           

    Electron microscopic examination of human fibroblasts,         
irradiated with pulsed, 3 MHz ultrasound at an SATP intensity of   
0.5 W/cm2 (duty factor 0.2), revealed more free ribosomes,         
increased dilation of the rough endoplasmic reticulum, increased   
damage to mitochondria and to lysosmal membranes, and more         
cytoplasmic vacuolation (Harvey et al., 1975).  Exposure of HeLa   
cells to 0.75 MHz ultrasound at an intensity of 0.9 W/cm2 for      
20-120 s caused slits in the cells, holes in the nuclear membranes,
separation of the inner and outer nuclear membranes, increase in   
cell debris, exploded mitochondria, and lesions of the endoplasmic 
reticulum (Watmough et al., 1977).  The results suggested that some
of the damage, such as rupture of the nuclear and plasma membranes,
may have been due to shear stresses resulting from microstreaming  
around oscillating microbubbles.                                   

Table 9.  Ultrastructural changes following  in vivo exposure to 
ultrasound                                                          
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
100     (cw)  15         damage to luminal aspect    Dyson et al.
                         of plasma membrane, cell    (1974)
                         debris (chick embryo)

1000    -     10         membrane changes, swollen   Dumontier et 
                         mitochondria, cell debris   al. (1977)
                         (rat testes)

1000    (cw)  9.1        changes in mitochondria     Stephens et 
                         (mouse liver, pancreas,     al. (1978)
                         kidney)

1000    (cw)  10         membrane changes, changes   Hrazdira &
                         to mitochondria             Havelkova 
                         (germinating spores of      (1966)
                          Rhizopus nigricans)

1000    (cw)  20         swollen basal labyrinth,    Pincuk et al.
                         microvilli, & mitochondria  (1971)
                         (dog kidney)

2000    (cw)  1          necrosis, haemorrhage       Valtonen
                         (mouse liver)               (1967)

2500    (cw)  5          vacuolation, necrosis,      Fallon et al.
                         desquamation, and mural     (1973)
                         thrombosis (rabbit
                         arteries)

3000    (cw)  5          increase in lysosome        Majewski et 
              (multiple) destruction (rat liver)     al. (1966)

3000    (cw)  5          increase in lysosome        Jankowiak &
                         destruction (rabbit liver)  Majewski 
                                                     (1966)

3500    (cw)  3          necrosis, intracytoplasmic  Karduck &       
                         vacuolation, destroyed      Wehmer
                         mitochondria (rabbit        (1974)
                         larynx)
-------------------------------------------------------------------

    Cachon et al. (1981) conducted studies on the microtubule      
system of a Heliozoan, using a commercial pulsed diagnostic device 
emitting 2.5 mW/cm2 for 10-20 s at 5 MHz.  The microtubules became 
disorganized within their axopods after exposure to ultrasound and 
the organisms stopped moving and died rapidly.  Electronmicroscopic
examination of human blood lymphocytes exposed for 30 min to cw 870
kHz ultrasound at 4 W/cm2 also revealed disruption of microtubule  
formation (Repacholi, 1982).                                       
                                                                   
    Results of studies on human lymphocytes and Erlich ascites     
carcinoma cells suggested a possible disturbance of the mitotic    
spindle at metaphase following ultrasound exposure (Schnitzler,    
1972).  Clarke & Hill (1970) reported that, in L51784 cells, the   
susceptibility to ultrasonic disintegration increased during       
mitosis.  It was suggested that cells are particularly susceptible 
to damage by ultrasound during mitosis, because major changes in   
the cell membrane and in internal structure occur during this phase
of the cell cycle.                                                 

Table 10.  Ultrastructural changes following  in vitro exposure 
to ultrasound
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
15      (p)   30         ultrastructural changes     Liebeskind et
                         (3T3 fibroblast cells &     al. (1981b)
                         rat peritoneal fluid cells)   

15      (p)   30         increase in number of       Liebeskind et
                         microvilli (mouse 3T3       al. (1981a)
                         cells)

500     (p)   5          damage to lysosomes,        Harvey et al.
                         mitochondria, cytoplasmic   (1975)
                         vacuoles (human
                         fibroblasts)

800     (cw)  5          increased platelet          Chater &
                         aggregation (human blood)   Williams 
                                                     (1977)

900     (cw)  0.3-2      damaged plasma & nuclear    Watmough et 
                         membranes, increased cell   al. (1977)
                         debris (HeLa cells)

2000    (cw)  2          rupture of myofibrils       Samosudova &
                         (chicken muscle)            El'piner 
                                                     (1966)

2600    (cw)  40         deformed erythrocytes       Koh (1981)
                         (human blood)
-------------------------------------------------------------------

    When a 3T3 fibroblast cell line and normal rat peritoneal fluid 
cells were exposed to pulsed 2 MHz ultrasound at l5 mW/cm2 for 30 
min post-sonication ultrastructural changes were observed (Liebeskind 
et al., 1981b).  The authors concluded that low-intensity, pulsed 
ultrasound could alter both cellular ultrastructure and metabolism. 
They suggested that the persistence of disturbances in cell motility, 
many generations after sonication  in vitro, is especially important 
and it can be speculated that, if fetal cells were to be subtly 
damaged, it might affect cell migration during organogenesis. 

    Results of  in vivo studies designed to observe cell membrane 
and intracellular changes (Tables 9 and 10) have, in general, been 
the same as those of  in vitro studies.  Mitochondria appear to be 
some of the intracellular organelles most sensitive to ultrasound 
exposure, exhibiting swelling, loss of cristae, and eventual 
disruption of the outer membrane.  The endoplasmic reticulum seems 
to be less sensitive to ultrasound exposure than mitochondria, but, 
with increasing exposure times, dilation of the cisternae, loss of 
surface ribosomes, and vesiculation occurs.  Most cell damage from 
sublethal exposures appears to be reparable within four days; 
however, changes in the mitochondria persist for longer periods of 
time and may be irreversible (Stephens et al., l978). 

6.3.1.5.  Summary

    In summary, exposure to ultrasound can cause changes in the 
ultrastructure of cells in culture, which lead to disruptions in 
macromolecular synthetic pathways.  Certain structural components 
may be susceptible to damage; these include the nuclear, lysosomal, 
and plasma membranes, microtubules, the mitotic spindle, and the 
endoplasmic reticulum.  Both ultrastructural and functional changes 
in the plasma membrane have been reported following exposure to 
relatively low-intensity pulsed ultrasound.  Because of the 
importance of the cell surface in such functions as immune 
determination, receptor topography carrier systems, and cell-cell 
recognition, these changes could have quite important ramifications 
 in vivo. 

    Though cavitation appears to be the dominant mechanism 
responsible for many of the ultrasonically-induced structural 
changes, it seems possible that some of these effects could be 
caused by noncavitational mechanical stresses.  The high acoustic 
intensities associated with pulsed ultrasound may be of importance 
in the effects observed.  The interpretation of the reported 
effects of pulsed ultrasound exposure on SCE production  in vitro
and its possible application to  in vivo situations is not known. 

6.3.2.  Effects of ultrasound on mammalian cell survival and
proliferation

    Ultrasound at sufficiently high intensities can generate 
cavitational activity that completely destroys microorganisms, 
viruses, bacteria, and animal and plant cells (Kato, 1969; Clarke & 
Hill, 1970; Coakley et al., 1971; Hill, 1972a, b; Kishi et al., 
1975; Kaufman et al., 1977; Li et al., 1977; Moore & Coakley, 

1977).  Ultrasonic disruption of cells at high intensities has also 
been demonstrated, both  in vitro and  in vivo (Fry et al., 1970; 
Taylor & Pond, 1970, 1972; Dunn & Fry, 1971; Lele & Pierce, 1972). 

    Many studies concerning the cellular effects of ultrasound 
have had qualitative biological end-points such as cell lysis or 
morphological changes in cell structure.  From the mid-1970s, how-
ever, investigators began to focus their attention on quantifiable 
biological variables such as cell survival and proliferative 
capacity.  Lysis of mouse lymphoma cells in suspension, at ultra-
sound frequencies and intensities used in clinical medicine, has 
been documented and correlated with acoustic cavitation (Coakley et 
al., 1971).  Maeda & Murao (1977) found significant growth 
suppression in human amniotic cells in culture exposed to cw 2 MHz 
ultrasound at intensities higher than 0.8 W/cm2 for 1 h.  Maeda & 
Tsuzaki (1981) also observed growth suppression in cultured human 
amniotic cells exposed to pulsed, 2 MHz ultrasound at SATA 
intensities higher than 60 mW/cm2 (1 kHz pulse repetition rate, 
3-Ás duration, 80 W/cm2 SPTP intensity). 

    The importance of peak pulse intensities and other parameters, 
such as pulse duration and pulse repetition frequency, has been 
reported by other investigators (Barnett, 1979; Sarvazyan et al., 
1980).  It has been suggested that intact cells surviving ultra-
sound exposure remain unaffected, in terms of subsequent growth and 
proliferation rates (Clarke & Hill, 1969).  However, other studies 
have shown that many of the intact nonlysed cells remaining after 
ultrasound exposure of mammalian cells in suspension are non-
viable, as determined by both vital dye exclusion and colony-
forming ability (Kaufman et al., 1977). 

    Exposure of HeLa and CHO cells for 2-5 min to cw 1 MHz ultra-
sound resulted in a threshold for cell lysis at an intensity of 
approximately 1 W/cm2, with the maximum effects occurring at an 
intensity of 10 W/cm2 (Kaufman et al., 1977).  Colonies formed from 
sonicated cells contained fewer cells and a higher frequency of 
giant cells than colonies formed from appropriate controls (Miller 
et al., 1977). 

    Kremkau & Witcofski (1974) reported a significant reduction in 
the rate of occurrence of mitotic cells in surgically stimulated 
rat liver exposed  in vivo to cw 1.9 MHz ultrasound at an intensity 
of 60 mW/cm2.  However, Miller et al. (1976a) were unable to confirm 
these findings with the same biological system exposed for 1 and 5 
min to 2.2 MHz ultrasound at intensities in the range of 0.06-16 
W/cm2.  One possible explanation for the differences in the results 
obtained in these studies was that the second method involved a 
circular motion of the transducer over the animal's ventral 
surface, while the transducer was kept stationary in the first 
case.  Negative results were also obtained by Barnett & Kossoff 
(1977), when they exposed regenerating rat liver to pulsed, 2.5 MHz 
ultrasound, 10-50 kHz pulse repetition rate and a temporal peak 
intensity of 33 W/cm2. 

    Ultrasound exposure of cells in suspension has been shown to 
induce both immediate and delayed effects (Kaufman & Miller, 1978). 
Studies performed at elevated temperatures showed that immediate 
cell lysis was independent of temperature (up to 43░C), whereas 
cellular inactivation (as measured by a reduction in plating 
efficiency) was temperature dependent (Li et al., 1977).  These 
studies indicate that immediate cell death may be caused by 
large-scale cellular damage (probably resulting from some form of 
cavitational activity), whereas the delayed effects depend on the 
cell's ability to repair sublethal damage.  These repair mechanisms 
are less efficient at elevated temperatures. 

    It appears that there is quite a wide range of "threshold 
intensities" for the lysis of isolated cells in suspension. 
Variables contributing to this wide variation include:  the gas 
content of the medium; exposure geometry; ultrasound exposure 
parameters; and the number and availability of cavitation nuclei. 
In any given medium, the last of these factors depends critically 
on the treatment of the medium immediately prior to exposure and 
the degree of agitation during exposure (Williams, 1982a). 

6.3.3.  Synergistic effects

    Variable results have been obtained following combined exposure 
to ultrasound and X-rays, including:  increases in cell death; 
increases in chromosomal aberration; reduction in the ionizing 
radiation dose needed to achieve tumour remission; and increases in 
cell membrane effects. 

    As an example of divergent results, Todd & Schroy (1974) 
reported that ultrasound (920 kHz, 0.14 W/cm2), administered within 
10 min of X-irradiation, decreased the dose of 50 kVp X-rays 
required to prevent 99% of cultured Chinese hamster cells from 
forming colonies.  In contrast, exposure of L5178Y mouse lymphoma 
cells in suspension to ultrasound did not have any significant 
effect on the survival of these tumour cells, either alone or by 
altering the response to X-rays (Clarke et al., 1970).  Kunze-Muhl 
(1981) treated human lymphocytes with cw ultrasound at 20 mW/cm2 
and 3 W/cm2 and also 20 mW/cm2 in combination with X-ray exposure, 
and observed variable increases in chromosomal aberration frequency 
depending on whether the ultrasound was given before or after 
X-irradiation. 

    In a preliminary communication, Burr et al. (1978) reported a 
highly significant (P<0.00001) relative increase in the number of 
chromosome aberrations observed in human lymphocytes  in vitro when 
ultrasound was administered at the same time as, or immediately 
after, 2 Gy of Gamma irradiation.  This synergistic effect was not 
observed when the ultrasound (cw 1 MHz, 2W/cm2 for 30 min) was 
given either before the gamma rays or more than 2 h afterwards. 

    In another study, the exposure of tumour cells to ultrasound 
and X-rays reduced the electrophoretic mobility of the cells by 30% 
(Repacholi, 1970).  The author proposed that ultrasound and X-rays 

might have been capable of shearing the mucopolysaccharide coat 
from the tumour cell, thus enhancing the potential for tumour-cell 
killing by lymphocytes. 

6.3.4.  Summary

    Ultrasound exposure apparently alters both cellular ultra-
structure and metabolism.  Cells exposed to ultrasound appear to be 
more prone to cell death during mitosis.  Supression of cellular 
growth has been reported under cw and pulsed exposure conditions. 
Cellular and molecular effects of ultrasound at low SATA intensities 
are given in Table 11, where many of the effects have resulted from 
pulsed exposures.  This, of course, could be at least partially due 
to other non-acoustic factors, where, for example at studies in 
which these effects were observed involved more sensitive end-
points. 

Table 11.  Cellular and molecular level effects
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
less    (p)   7.5 to     increased rate of sister    Haupt et al.
than          90         chromatid exchange          (1981)
0.1                      (lymphocytes)

0.9     (p)   0.5        attachment of cultured      Siegel et al.
                         human cells                 (1979)

2.5     (p)   0.3        disorganization of          Cachon et al.
                         microtubules                (1981)

2.61    (p)   30         alterations of electro-     Hrazdira & 
                         kinetic potential and       Adler (1980)
                         erythrocyte agglutination

2.7     (p)   30         increased rate of sister    Liebeskind et 
and                      chromatid exchange          al. (1979b)
5.0                      (lymphocytes)

10      (cw)  30 and     no change in rate of        Wegner et al.
              90         sister chromatid exchange   (1980)
                         (Chinese hamster ovary
                         cells)

15      (p)   up to      unscheduled non-S-phase     Liebeskind et 
              40         (repair) DNA synthesis      al. (1979a)

15      (p)   up to      disturbances in cellular    Liebeskind et 
              40         growth pattern              al. (1979a)
-------------------------------------------------------------------

Table 11  (contd.)
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
15      (p)   30         ultrastructural changes     Liebeskind et 
                         (mouse fibroblasts and      al. (1981a)
                         rat peritoneal cells)

15      (p)   30         changes in topography of    Liebeskind et 
                         cell surface                al. (1981a)

15      (p)   30         hereditary changes in       Liebeskind et 
                         cell mobility (mouse        al. (1981b)
                         fibroblasts)

20      (cw)  10         increase in chromosomal     Kunze-Muhl
                         aberrations when given      (1981)
                         before X-ray exposure

40      (cw)  3          altered visco elastic       Johnson &
                         properties ( Elodea cells)   Lindvall 
                                                     (1969)

60      (p)   30         suppression of cell growth  Maeda & 
                                                     Tsuzaki 
                                                     (1981)

200     (cw)  15         damage to DNA (calf         Galperin-
                         thymus)                     Lemaitre et           
                                                     al. (1975)

200     (cw)  5          increase in protein         Belewa- 
                         synthesis (hepatic, renal,  Staikowa &  
                         and myocardial tissue)      Kraschkowa
                                                     (1967)

250     (cw)  0.5        changes in topography of    Martins
                         cell surface (m3-1 cells)   (1971)

400     (cw)  3          degradation of DNA (calf    Hill et al.
                         thymus and salmon sperm)    (1969)

500     (cw)  10         changes in protein          Bernat et al.
                         metabolism                  (1966a)

500     (cw)  5          ultrastructural changes     Harvey et al.
                         (human fibroblasts)         (1975)

500     (p)   5          ultrastructural changes     Harvey et al.
                         (human fibroblasts)         (1975)
-------------------------------------------------------------------

Table 11  (contd.)
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
500     (cw)  5          increase in permeability    Lota & 
                         of human erythrocyte mem-   Darling
                         branes to potassium ions    (1955)

600     (cw)  30         decrease in transport of    Bundy et al.
                         leucine in avian            (1978)
                         erythrocytes

800     (cw)  60         suppression of cell         Maeda & Murao
                         growth                      (1977)

900     (cw)  0.3        ultrastructural changes     Watmough et 
                         (HeLa cells)                al. (1977)

1000    (cw)  5          retarded protein            Belewa-          
                         synthesis                   Staikowa &
                                                     Kraschkowa
                                                     (1967)

3000    (cw)  10         increase in chromosomal     Kunze-Muhl
                         aberrations when given      (1981)
                         after X-ray exposure

36 000  (cw)  10         no sister chromatid         Morris et al.
                         exchanges                   (1978)
-------------------------------------------------------------------

6.4.  Effects on Multicellular Organisms

6.4.1.  Effects on development

    To date, most of the work on the effects of ultrasound on 
development has been carried out on  Drosophila melanogaster, the 
mouse, and the rat. 

6.4.1.1.  Drosophila melanogaster

    Many studies have been performed on the eggs, larvae, and 
prepupal stages of  Drosophila melanogaster and a variety of 
abnormal developmental effects have been observed in the adult 
flies (Fritz-Niggli & Boni, 1950; Selman & Counce, 1953; Child et 
al., 1981a, b).  With the possible exception of eggs in the early 
stages of development, all insects contain microscopic, stable gas 
bodies throughout their life cycle.  These gas bodies oscillate 
under the influence of the ultrasound and presumably generate 
streaming motions in adjacent soft tissues, that are probably 
responsible for the observed effects.  The results of these studies 
may not be applicable to mammalian systems, which apparently do not 
contain stable gas bodies of comparable dimensions. 

6.4.1.2.  Mouse

    Much of the work conducted on developmental effects in mice has 
been concerned with the use of very high ultrasound intensities and 
the observed effects were most probably due to heating.  Such 
studies are of very limited value for a health risk assessment from 
ultrasound exposure and have therefore not been included. 

    Early mouse morulae (2-4 cell embryos) were exposed to 
focused and pulsed diagnostic ultrasound  in vitro (2.25 MHz, 2.2 
mW/cm2, repetition rate 500 Hz, pulse duration 3 Ás) for 12 h; no 
suppression of growth was observed (Akamatsu & Sekiba, 1977).  Hara 
et al. (1977) exposed 8-day-old mouse embryos to pulsed ultrasound 
(2 MHz, pulse duration 180 Ás, repetition rate 150 Hz) for 5 min.  
The animals received SATA intensities of either 50 mW/cm2 or 600 
mW/cm2; an increased incidence of fetal malformations was observed 
following the higher intensity exposure.  At this higher intensity 
(SPTP intensity 22 W/cm2), a temperature rise of about 3 ░C was 
measured.  The authors also reported a significant reduction in 
maternal weight following exposure to ultrasound. 

    When 8-day-old mouse embryos were exposed to ultrasound  in
 utero (cw 1 MHz, SATA intensities 0.5-5.5 W/cm2, 10-300 s), a
statistically significant reduction in fetal weight was observed 
(O'Brien, 1976).  This observation was confirmed by Stolzenberg 
et al. (1980a) using cw 2 MHz ultrasound at SATA intensities of 0.5 
and 1 W/cm2 for 1-3 min.  Threshold conditions reported to produce 
a decrease in the mean uterine weight in the progeny were 0.5 W/cm2 
for 140 s or 1 W/cm2 for 60 s (Stoltzenberg et al., 1980b).  
However, temperature measurements showed that the uterine 
temperature was elevated to more than 44 ░C, indicating that damage 
was due to a thermal mechanism.  In these studies, hind-limb 
paralysis and distended bladder syndrome were observed in the 
mothers at laparotomy and this may have been a contributing factor 
in the reported weight loss in the mothers and offspring 
(Stolzenberg et al., 1980c).  Reduced fetal body weight has also 
been reported by Tachibana et al. (1977) following exposure to cw 
2.3 MHz ultrasound at SATA intensities of 80-100 mW/cm2, and by 
Stratmeyer et al. (1979, 1981a), who used cw 1 MHz ultrasound for 2 
min at a SATA intensities of 75-750 mW/cm2.  Growth-inhibiting 
effects on fetuses were reported by Shoji et al. (1975) in one of 
two strains of mice following a 5-h exposure to cw 2.25 MHz 
ultrasound at an intensity of 40 mW/cm2.  However, Edmonds (1980) 
contends that the calculated free-field intensity for these 
experiments was closer to 280 mW/cm2. 

    An increased incidence in fetal abnormalities was observed 
after a 5-min exposure  in utero to cw ultrasound of approximately 
2 MHz, at a SATA intensity of 1.4 W/cm2, but not at SATA intensities 
of 0.5 or 0.75 W/cm2 (Shimizu, 1977).  Hara (1980) also found fetal 
malformations after an  in utero exposure to cw 2 MHz ultrasound 
at 2 W/cm2 for 5 min; the uterine temperature rose to 41.5 ░C.  
Similar results were obtained using pulsed, 2 MHz ultrasound (SATA 
intensity 296 mW/cm2, pulse duration 5 ms, repetition rate 1 kHz, 
SATP intensity 59.4 W/cm2), but not at lower SATA intensities or 

shorter pulses (Takabayashi et al., 1980).  A significant increase 
in skeletal abnormalities was observed in two strains of mice 
subjected to the same ultrasonic exposure (cw 2.25 MHz, SATA 
intensity 40 mW/cm2, for 5 h), but visible malformations were 
only present in one of the strains (Shimizu & Shoji, 1973). 

    Curto (1975) observed an increased mortality rate in the mouse 
offspring exposed  in utero to cw 1 MHz ultrasound at SATA intensities 
of 0.125, 0.25, and 0.5 W/cm2, for 3 min.  However, Edmonds et al. 
(1979) did not find any effects on neonatal mortality after 
exposure to cw 2 MHz ultrasound at a SATA intensity of 0.44 W/cm2, 
for a similar exposure time but at a different gestational age. 

6.4.1.3.  Rat

    The development of pre-implantation morulae and early 
blastocysts of rat was suppressed after exposure to cw 2 MHz ultra-
sound at 1 W/cm2, and necrotic changes occurred after exposure at 3 
W/cm2 (Akamatsu et al., 1977).  Suppressed development was also 
noted in early embryos after exposure to pulsed 2 MHz ultrasound 
(10 ms, SATA intensity 0.6 W/cm2, SPTP intensity 220 W/cm2), 
how ever, development progressed normally after exposure to an SATA 
intensity of 20 mW/cm2 (Akamatsu, 1981). 

    An extrapolated threshold intensity of about 3 W/cm2 was found
to be lethal for rat fetuses  in utero, subjected to cw 0.71 or 3.2 
MHz ultrasound for 5 min (Sikov et al., 1976).  The susceptibility 
of the fetuses depended on the gestational age at the time of 
exposure.  Increased fetal anomalies without corresponding 
decreases in fetal weights were reported by Sekiba et al. (1980) 
following exposure to cw 2 MHz ultrasound (SATA intensities 1.5 
and 2.5 W/cm2) for 15 min.  In a study by Sikov et al. (1977), rat 
fetuses were exposed  in utero to cw 0.93 MHz ultrasound (SATA 
intensities of 0.01-1 W/cm2) for 5 min; an increased incidence of 
prenatal mortality and delayed neuromuscular development were 
found.  However, the authors did not find any evidence of increased 
postnatal mortality or reduced growth rate.  A slight (but not 
statistically significant) increase in skeletal variations and 
resorption rates was reported by McClain et al. (1972) following  in 
 utero exposure to cw 2.5 MHz ultrasound at an SATA intensity of 10 
mW/cm2 for 0.5 or 2 h, at various gestational ages.  No significant 
differences were observed in viability, body weight, litter size, 
implantation, and skeletal or soft tissue abnormalities. 

    Pulsed ultrasound exposures were reported to have caused an 
increased incidence of gross and microscopic heart anomalies in rat 
fetuses exposed to 2.5 MHz at SATA intensities greater than 0.5 
W/cm2 or SATP intensities greater than 50 W/cm2 (Sikov & Hildebrand, 
1977).  More extensive studies failed to confirm the occurrence of 
cardiac anomalies but did confirm changes in neuromuscular 
development at SATA intensities greater than 0.5 W/cm2 (Sikov, 
personal communication).  Takeuchi et al. (1966) did not find any 
significant increase in the number of malformations or any change 
in fetal weight in rat fetuses exposed  in utero to a pulsed, 1 MHz 
clinical apparatus.  Similar negative results were reported by 

Shimizu & Tanaka (1980), who exposed pregnant Chinese hamsters to 
pulsed, 2 MHz ultrasound (3-Ás pulses, 1 kHz repetition rate, SATA 
intensity 200 mW/cm2, SATP intensity 67 W/cm2) for 5 min on days 8,
9, and 10 of gestation. 

6.4.1.4.  Frog

    Sarvazyan et al. (1980) exposed explants of embryos of  Rana 
 temporaria, at different stages of development, to 1 MHz ultrasound 
(SATA intensity 50 mW/cm2, pulse repetition frequencies in the 
kilohertz range, duty factor, 0.5).  Local necroses and complete 
blockage of gastrulation, observed after 15 min exposure, were 
highly dependent on the pulse repetition frequency.  The ultrasound 
did not seem to be as effective in inducing effects after 
gastrulation had occurred. 

6.4.1.5.  Summary

    Reports on the effects of ultrasound on animal development are 
summarized in Tables 12 and 13. 

Table 12.  Weight reduction in mice
-------------------------------------------------------------------
SATA             Total
intensity        exposure  Effect observed          Reference
(mW/cm2)         time
                 (min)
-------------------------------------------------------------------
2000    (cw)     5         reduced maternal weight  Hara, et al.
                                                    (1977, 1980)

1000    (cw, p)  8.8       reduced fetal weight     Stolzenberg et 
                                                    al. (1980a)

500 -   (cw)     0.16-5    reduced fetal weight     O'Brien (1976)
5000                                                

500 -   (cw)     1-3       reduced fetal weight     Stolzenberg et 
1000                                                al. (1980b)

80      (cw)     8         reduced fetal weight     Tachibana et 
                                                    al. (1977)

75      (cw)     2         reduced fetal organ      Stratmeyer et 
                           weight                   al. (1979, 
                                                    1981)

50      (p)a     5         reduced maternal weight  Hara et al. 
                                                    (1977)
-------------------------------------------------------------------
a   22 W/cm2 Temporal Peak Intensity.

Table 13.  Exposures at which reports on fetal abnormalities have 
been reported in rodents
-------------------------------------------------------------------
SATA             Total
intensity        exposure  Effects reported         Reference
(mW/cm2)         time
                 (min)
-------------------------------------------------------------------
3000    (cw)     5         fetal abnormalities and  Sikov & 
                           prenatal death threshold Hildebrand
                           (rats)                   (1977)

2000    (cw)     5         increase in fetal        Hara et al.
                           malformations (mice)     (1977, 1980)

1400    (cw)     5         fetal abnormalities      Tachibana et 
                           (mice)                   al. (1977)

1400    (cw)     5         fetal abnormalities      Shimizu (1977)
                           (mice)                   

600     (p)a     5         fetal abnormalities      Hara et al.
                           (mice)                   (1977)

586     (p)a     5         fetal abnormalities      Takabayashi et
                           (mice)                   al. (1980)

500     (p)b     5         fetal heart              Sikov & 
                           abnormalities (rat)d     Hildebrand 
                                                    (1977)

296     (p)      5         fetal abnormalities      Takabayashi et 
                           (mice)                   al. (1980)

125     (cw)     3         postpartum mortality     Curto (1975)
                           (mice)                   

40      (cw)c    300       fetal abnormalities      Shoji et al.
                           (mice)                   (1975)

10      (cw)     30        skeletal variations      McClain et al.
                           (rats)e                  (1972)
-------------------------------------------------------------------
a   22 W/cm2 Temporal Peak Intensity.
b   50 W/cm2 Temporal Peak Intensity.
c   This exposure was in air; the calculated equivalent free field
    intensity in a water bath has been suggested to be 280 mW/cm2 
    by Edmonds (1980).
d   Not statistically significant and not confirmed in a more 
    extensive study by the same investigators.
e   Not statistically significant.

    These reports are difficult to interpret and, in most cases, to 
compare directly, partly because of differences in the organism 
used, the state of fetal development at the time of exposure, and 
the exposure variables.  The published works show that, if the 
intensity is sufficiently high, death or some type of anatomical 
abnormality will result in certain organisms.  Ultrasound is known 
to raise the temperature of biological samples by which it is 
absorbed.  The effects of exposure at therapeutic intensities 
(O'Brien, 1976; Stolzenberg et al., 1978; Torbit et al., 1978) are 
most likely due to hyperthermia (Lele, 1975).  Hyperthermal effects 
in rats and mice depend on the stage of development and exposure 
conditions, and include fetal resorption, retardation of growth, 
exencephaly, and defects of the tail, limbs, toes, and palate. 

    In Table 12, the lowest levels at which fetal weight reduction 
occurred are in the range 50-80 mW/cm2.  Within this intensity 
range and under the experimental conditions used in these 
investigations, the effects are less likely to be due to hyper-
thermia.  Furthermore, the results of a study by Sarvazyan et al. 
(1980) suggest that the biological effects induced by pulsed ultra-
sound may be critically dependent on the pulse repetition rate as 
well as on the acoustic intensity. 

6.4.2.  Immunological effects

    Effects of ultrasound on the immune response have not been 
extensively investigated. 

    Anderson & Barrett (1979) reported a slight, dose-dependent 
immunosuppressive effect in mice exposed to 2 MHz ultrasound at a 
SATA intensity of 8.9 mW/cm2 (SPTP intensity 28 W/cm2), applied 
over the area of the spleen.  However, the complexity of this 
response, and the imprecision of the assay techniques used warrant 
cautious interpretation of these data.  Child et al. (1981c) using 
a similar exposure regime were unable to confirm the findings of 
Anderson & Barrett (1979). 

    Mice sonicated over the liver with pulsed 2 MHz diagnostic
ultrasound (pulse repetition rate 691 Hz, exposure time 1.6, 3.3, 
and 5 min, SATA intensity 8.9 mW/cm2) had an impaired ability to 
clear injected colloidal carbon from their blood (Anderson & 
Barrett, 1981).  The phagocytic index and clearance half-time were 
not lower than normal, immediately after treatment, but were lower, 
48 or 72 h after sonication.  In a similar experimental arrangement, 
Saad & Williams (1982) found that SATA intensities of cw 1.65 MHz 
ultrasound greater than 0.7 W/cm2 were needed before a reduction in 
the rate of clearance of colloidal sulfur particles from rat blood 
could be detected  in vivo. 

    Other evidence of immunological effects have been reported 
by Kiski et al. (1975), Bekhame (1977), and Koifman et al. 
(1980).  In addition, Pinamonti et al. (1982) observed a loss of 
erythrocyte surface antigens following exposure to a pulsed 8 MHz 
ophthalmological ultrasound device at a SATA intensity of 2 mW/cm2, 
for 30 min (pulse repetition rate 744 Hz). 

6.4.2.1.  Summary

    It is extremely difficult to draw any firm conclusions on the 
effects of ultrasound on immunological response.  Both diagnostic 
and therapeutic levels have been reported to induce effects. 

6.4.3.  Haematological and vascular effects

6.4.3.1.  Platelets

    Blood platelets are extremely fragile cells which, if 
stimulated, aggregate and release substances that initiate the 
formation of a clot (Williams, 1974; Brown et al., 1975). 

    (a)   In vitro studies

    Ultrasound exposure at a frequency of 1 MHz reduces the
recalcification time of platelet-rich plasma at intensities as
low as 65 mW/cm2 (Williams et al., 1976a).  In a study by
Williams et al. (1976b), subsequent morphological analysis of 
recalcified clots revealed the presence of platelet debris, 
indicating that the ultrasound had apparently ruptured a small 
portion of the platelet population, releasing adenosine diphosphate 
(ADP) and other aggregating agents into the surrounding plasma.  
These agents then induced other platelets to release, resulting in 
a self-perpetuating cycle of platelet aggregation and release. 

    Numerous  in vitro studies have confirmed that the ultrasound-
induced mechanism responsible for platelet aggregation is some form 
of cavitational activity (Williams et al., 1976b, 1978; Chater & 
Williams, 1977; Miller et al., 1979). 

    A variety of threshold SATA intensities determined within the
range 0.6-1.2 W/cm2 were found to be critically dependent on the 
pretreatment and rate of stirring of the sample during sonication 
(Williams, 1982a).  The lowest thresholds were obtained when 
stabilized gas bubbles were deliberately introduced prior to 
exposure.  Using this system, Miller et al. (1979) detected platelet 
damage from cw 2.1 MHz ultrasound at SPTA intensities as low as 32 
mW/cm2, and also with a commercial cw Doppler device.  Using a burst 
(gated) regime (burst duration 1 ms, duty factor 0.1) reduced this 
threshold to an SPTA intensity of 6.4 mW/cm2 (Miller et al., 1979). 

    (b)   In vivo studies

    Little information exists in the literature on the effects of 
ultrasound on platelets  in vivo.  Williams (1977) demonstrated that 
shear stress forces, similar to those that might be generated  in 
 vivo by acoustic cavitation, could trigger platelet aggregation and 
the formation of thrombi within intact blood vessels in mice. 
Effects ranged from platelet adhesion to the endothelial walls of 
the blood vessel to clot formation and complete occlusion of the 
vessel.  Zarod & Williams (1977) found small platelet aggregates 
within the microcirculation of the guinea-pig pinna after  in vivo 
exposure to cw ultrasound of either 0.75 or 3.0 MHz for 2 min, at a 

SATA intensity of 1 W/cm2.  Platelets that had been only partially 
stimulated by ultrasound were less likely to respond to other 
stimuli, such as ADP, for a period of time (i.e., they had become 
refractory) (Chater & Williams, 1977).  Such an effect has also 
been reported  in vivo by Lunan et al. (1979), who found decreased 
aggregation of platelets after whole-body exposure of mice to cw 2 
MHz ultrasound at a SATA intensity of 1 W/cm2. 

    Plasma levels of beta-thromboglobulin (a human platelet-
specific protein) were measured by Williams et al. (1977, 1981) 
after  in vivo exposure to cw 0.75 MHz ultrasound at a SATA 
intensity of up to 0.5 W/cm2, but no changes were detected.

    Ultrasound-induced platelet effects could have serious clinical 
consequences.  For example, the production of platelet aggregates 
 in vivo might lead to the blockage of circulation in small 
capillaries and subsequent complications of embolism and infarction, 
especially in patients exhibiting clinical conditions that might 
predispose them to thrombosis (e.g., during pregnancy or after 
surgery).  However, some of these interactions may, in fact, be 
beneficial.  For example, Hustler et al. (1978) found inhibition of 
experimental bruising in the guinea-pig ear after exposure to 0.75 
MHz at 0.6 W/cm2. 

6.4.3.2.  Erythrocytes

    (a)  In vitro studies

    Red blood cells are less sensitive to rupture by shear stress 
than platelets (Nevaril et al., 1968; Rooney, 1970; Williams et 
al., 1970; Leverett et al., 1972).  Veress & Vineze (1976) reported 
that haemolysis occurred  in vitro at intensities as low as 200 
mW/cm2 (spatial average).  It was not determined whether this 
represented a threshold value, but a linear relationship existed 
between the logarithm of the time necessary to produce haemolysis 
at 1 MHz and the intensity of the ultrasound, at a given 
concentration of blood cells.

    In a study by Koh (1981), the blood of pregnant women was
exposed  in vitro to cw 20 mW/cm2 ultrasound for 2-12 h and 2.6 
W/cm2 for 40-120 min.  An increased free haemoglobin level was
reported only after exposure to the higher intensity.  Significant 
lysis of human erythrocytes exposed  in vitro for 6-8 h to Doppler 
ultrasound at intensities in the range of 10-20 mW/cm2 was reported 
by Takemura & Suehara (1977).  However, Kurachi et al. (1981) 
reported that haemolysis of human blood did not increase after  in 
 vitro exposure of 24 h to a pulsed diagnostic device or 60 min to 
pulsed 2 MHz ultrasound at 0.57 W/cm2 (10 Ás pulses, SATP intensity 
50 W/cm2, pulse repetition rate 1 kHz).

    Functional changes in human erythrocytes have been found after 
 in vitro exposures for 30 min to pulsed 8 MHz ultrasound at 2 mW/cm2. 
Irradiation appears to affect the erythrocyte membrane, causing a 
decrease in the oxygen affinity of the cells (Pinamonti et al., 
1982). 

(b)   In vivo studies

    Williams et al. (1977, 1981) were unable to detect haemolysis 
in human blood exposed  in vivo to unfocused cw 0.75 MHz ultrasound 
at a SATA intensity of 0.34-0.5 W/cm2, for an exposure time of 
about 30 s.  However, Wong & Watmough (1980) reported lysis of 
mouse erythrocytes  in vivo after they had irradiated the heart with 
0.75 MHz ultrasound at about 0.8 W/cm2.  This result is probably a 
reflection of the enhanced nucleation conditions existing within 
the beating heart.  Similar positive results  in vivo were reported 
by Yaroniene (1978), who exposed rabbit hearts to 2 MHz ultrasound 
in both the cw (SATA intensity 10 mW/cm2) and pulsed modes (pulse
duration 4 ms, repetition rate 1 kHz, SPTP intensity 90 mW/cm2, 
SATA intensity 0.4 mW/cm2) for prolonged exposures of up to one 
month.

6.4.3.3.  Blood flow effects

    An ultrasonic standing wave field can stop the flow of blood 
cells within intact blood vessels  in vivo (Schmitz, 1950; Dyson et 
al., 1971; ter Haar, 1977).  This effect was subsequently called 
"blood stasis" or "blood flow stasis" (Dyson et al., 1971).  Dyson 
& Pond (1973) and Dyson et al. (1974) found that the blood cells 
grouped into bands, spaced at half-wavelength intervals and 
separated by regions of clear plasma.  The bands were oriented in a 
direction perpendicular to that of the propagating ultrasound.  At 
3 MHz and high intensities, the minimum time for banding to occur 
in front of a perfect reflector was approximately 0.05 s.  The 
minimum intensity required for stasis was generally less than 
0.5 W/cm2 at 3 MHz and varied with the type, size, and orientation 
of blood vessels and with the animal's heart rate.  Electron 
microscopic examination revealed damage to some of the endothelial 
cells lining the blood vessels in which stasis had occurred.  With 
short exposure times, the effect and damage generally appeared to 
be reversible.  Permanent damage was observed following an extended 
exposure time of 15 min. 

    Blood flow stasis has also been observed in mouse uterine blood 
vessels (ter Haar, 1977; ter Haar et al., 1979).  The mechanism 
responsible for this phenomenon is the radiation force associated 
with the standing wave field (ter Haar & Wyard, 1978).  The authors 
observed that blood stasis did not occur when the transducer was 
moved over the irradiated tissue.  This is of obvious significance 
in the therapeutic use of ultrasound where it is normal practice to 
keep the transducer in motion during treatment. 

6.4.3.4.  Biochemical effects

    Various biochemical alterations have been reported following
 in vivo exposure of guinea-pigs (Straburzynski et al., 1965; Bernat 
et al., 1966a) and rats (Sterewa, 1977) to therapeutic levels of 
ultrasound.  Glick et al. (1981) reported chemical and haematological 
changes in the blood of mice following ultrasonic exposure.

6.4.3.5.  Effects on the haematopoietic system

    Haemorrhaging was observed in the bone marrow of canine femurs 
exposed to 500 mW/cm2 for 2 min (Bender et al., 1954).  Damage to 
the bone marrow was also observed by Payton et al. (1975), who 
exposed dog femurs to cw 875 kHz ultrasound at a SATA intensity of 
2.5 W/cm2, for 5 min each day, for 10 days over a 14-day period, 
using a slow stroking technique.  Exposure for 5 min to 2.5 W/cm2 
resulted in a 5 ░C increase in the temperature of the bone marrow 
cavity.  Using the same technique, a 10-min exposure resulted in 
gross changes, including an increased peripheral blood clotting 
time. 

6.4.3.6 Summary

    Some of the reported effects of ultrasound on blood are
summarized in Table l4.  Strong standing wave fields can stop 
the flow of blood in small blood vessels.  Prolonged stasis may 
cause irreversible endothelial and blood cell damage and the 
initiation of blood coagulation.  Blood cells in suspension  in 
 vitro are lysed at therapeutic intensities (around 1 W/cm2) and at 
lower intensities if the cell suspensions are stirred or agitated 
or if gas bubbles are deliberately introduced into the medium.  
Some functional effects on blood cells have been reported at 
diagnostic intensities, but these have not been independently 
confirmed and the mechanism of interaction that produces these 
effects is not known. 

6.4.4.  Genetic effects

    This section will cover the effects of ultrasound on chromosome 
aberrations, mutagenesis, and other indicators of genetic damage. 
For the purpose of this review, genetic effects will include 
heritable effects or indications of DNA damage in somatic cells as 
well as genetic cells. 

6.4.4.1.  Chromosome aberrations                                     
                                                                     
    A number of early studies (for review see Thacker, 1973)         
revealed that exposure to ultrasound induced chromosome aberrations  
in plant root tips.  In most studies, the damage was thought to be   
a result of cavitation or heating.  However, Slotova et al. (1967)   
reported chromosome aberrations in  Vicia faba root tips exposed to   
ultrasound intensities of 200-300 mW/cm2 for 1-20 min, with the      
number of aberrations returning to normal levels 24 h after          
irradiation.  Gregory et al. (1974) and Cataldo et al. (1973),       
using intensities of 1-20 W/cm2 for up to 2 min, did not observe     
any "classical" chromosome aberrations in  Vicia faba root tips.      
They did, however, report the appearance of bridged and agglomerated 
chromosomes in the exposed cells, but not in the control cells.      
The authors suggested that the standard chromosome aberrations       
scoring technique would not be suitable for the type of damage seen  
in these studies, because the "standard" technique is to choose      
only well-spread metaphase chromosomes for scoring.  The significance
of the bridged and agglomerated chromosomes is not known.            

Table 14.  Effects of ultrasound on the blood
-------------------------------------------------------------------
Ultrasound     Total      Effect observed          Reference
intensity      exposure                                            
               time
-------------------------------------------------------------------
4 W/cm2  (cw)  10 min     decreased glutathione    Straburzynski 
                          level and increased      et al. (1965)
                          ascorbic acid level
                          (guinea-pig,  in vivo)

65       (cw)  5 min      decrease in clotting     Williams et al.
mW/cm2                    time (human blood,       (1976a, 1976b)
                           in vitro)

32-64    (cw)  1 & 10     clumping in platelet     Miller et al.
mW/cm2         min        rich plasma (human       (1978)
SPTP                      blood,  in vitro)

6.4-12.5 (p)   1 & 10     clumping in platelet     Miller et al.
mW/cm2         min        rich plasma (human       (1978)
SPTA                      blood,  in vitro)

1 W/cm2  (cw)  200 s      biochemical and          Glick et al.
                          haematological           (l981)
                          changes (mouse,  in
                           vivo)

2 mW/cm2 (p)   30 min     Functional changes       Pinamonti et 
                          in erythrocytes (human,  al. (1982)
                           in vitro)
-------------------------------------------------------------------

    In the early 1970s, a number of studies were carried out on 
chromosome aberrations in human and other mammalian cells after 
ultrasound irradiation.  These studies were stimulated, at least 
in part, by Macintosh & Davey (1970, 1972), who reported the 
production of chromosome aberrations in human lymphocytes.  
However, in other studies, which covered a range of variables 
(frequency, intensity, duration of exposure, cell stage), there 
was not any evidence of chromosome aberrations after ultrasound 
exposure (Boyd et al., 1971; Buckton & Baker, 1972; Hill et al., 
1972; Watts et al., 1972; Rott & Soldner, 1973).  Two studies 
(Watts & Stewart, 1972; Galperin-Lemaitre et al., 1973) in which 
cells were exposed  in vivo also failed to show chromosome 
aberrations.  Furthermore, when Macintosh et al. (1975) tried to 
reproduce their earlier work as closely as possible, they were 
unsuccessful.  The preponderance of evidence suggests that 
diagnostic levels of ultrasound do not cause chromosome aberrations 
in mammalian cells, but this does not negate the possibility of 
other genetic damage. 

6.4.4.2.  Mutagenesis

    Thacker (1974) used the yeast  Saccharomyces cerivisiae to test 
for the genetic effects of ultrasound.  Two of the assays tested 
for mutations in nuclear genes, one for mutation in mitochondrial 
DNA, and one for recombination of a nuclear gene.  The exposure 
variables were similar to those used in diagnostic ultrasound (peak 
intensity of 10 W/cm2, using 20-Ás pulses and a duty factor of 
0.004) or therapeutic ultrasound (cw 5 W/cm2, for up to 30 min). 
Tests were also made under more severe conditions than those found 
in medical applications.  None of these exposures showed any 
evidence of increased mutations or recombination after ultrasound 
exposure, except under conditions where heat or hydrogen peroxide 
was allowed to accumulate. 

    In another mutation study, Thacker & Baker (1976) tested for 
evidence of mutation in  Drosophila melanogaster after exposure to 
diagnostic levels of ultrasound.  There was no evidence of lethal 
recessive mutations or non-disjunction with ultrasound intensities 
up to 2 W/cm2, even though these levels were high enough to kill 
considerable numbers of flies. 

    Bacteria have also been used to test for mutation induction 
after exposure to ultrasound.  Combes (1975) used  Bacillus subtilis 
to test for reversion of an auxotrophic mutant after ultrasound 
exposure.  No mutants were seen in this system after exposure to 
pulsed, 2 MHz ultrasound at intensities of up to 60 W/cm2. 

    Genetic damage was studied in mice, in which the gonads had 
been exposed to cw or pulsed 1.5 MHz ultrasound at 1 W/cm2 (Lyon & 
Simpson, 1974).  The authors tested for induction of translocations 
of chromosome fragments in spermatocytes and for the induction of 
dominant lethal mutations in females.  The tests were negative, but 
because of sample variation and the small number of animals used, 
only pronounced mutagenic effects would have been observed. 

    Liebeskind et al. (1979a) found that ultrasound affected 
several test systems in cultured mammalian cells, suggesting 
possible genetic damage.  A diagnostic ultrasound device was used, 
and cells were exposed to pulsed 2.5 MHz ultrasound for 20-30 min 
at a SPTP intensity of 35.4 W/cm2.  One test system involved 
antinucleoside antibodies, which are specific for single-stranded 
or denatured DNA, are normally bound only during the DNA synthesis 
or S-phase, and have low binding during the G-1 phase.  After 
ultrasound exposure, the cells showed increased binding during the 
G-1 phase, though there was no evidence of strand breakage as 
indicated by alkaline-sucrose gradient ultracentrifugation. 

    Another test system used in this study was the incorporation 
of 3H-thymidine into non-S-phase cells as a measure of repair 
synthesis.  Exposure to ultrasound resulted in an increased 
labelling in the non-S-phase cells, suggesting an increase in 
repair synthesis.  There was, however, no evidence of an increase 
in SCE in HeLa cells (section 6.3.1.2).  In the same study, 
Liebeskind et al. (1979a) investigated the effects of ultrasound 

exposure on the morphological transformation of 10T-1/2 cells and 
found that it resulted in the induction of type II morphological 
transformants, both with and without the promoter TPA. 

    In a subsequent study, Liebeskind et al. (1979b) reported that 
diagnostic levels of pulsed 2.25 MHz ultrasound induced small, but 
significant, increases in SCE in fresh human lymphocytes as well as 
in a human lymphoblast line.  The significance of SCE is unknown, 
but it does appear to reflect chromosome damage.  The increased 
SCEs reported in this paper following exposure to high SPTP, low 
SATA intensities of pulsed ultrasound are consistent with the 
findings of Haupt et al. (1981) but contrary to the findings of 
Morris et al. (1978) and Wegner et al. (1980), who used cw exposure 
conditions.  Morris et al. (1978) exposed human leukocytes to cw 1 
MHz ultrasound at intensities of 15.3-36 W/cm2 for 10 min.  No 
increase in SCE was observed after exposure. 

    Hereditary changes were observed in cell surface characteristics 
(persisting for 50 generations in culture) and cell mobility 
(persisting for 10 generations after a single exposure to ultra-
sound) (Liebeskind et al., l981 a,b).  Moreover, changes in cell 
growth regulation (transformation assays) suggest that genetic 
damage does occur after  in vitro exposure of cell suspensions to 
pulsed diagnostic ultrasound.  It is not clear how these results 
can be interpreted in terms of  in vivo exposure or extrapolated to 
human exposure.  The observed immunoreactivity suggests disturbances 
in cellular DNA, but other interpretations are possible.  The 
density gradient analysis does not appear to indicate DNA strand 
breakage, but the transformation data suggest possible genetic 
damage. 

    Three types of abnormal morphology of transformed cells have 
been described (Reznikoff et al., 1973).  The cells used in this 
study initially had type I morphology and the ultrasound treatment 
transformed a few of the colonies to type II morphology.  Because 
transformation does not appear to be a sudden event, but rather a 
progression of changes (or stages), and because the transformation 
seen in this study is apparently only a part of that progression, 
it does not necessarily follow that genetic damage has occurred.  
It is significant, however, that ultrasound had an effect on the 
process of transformation. 

    Fahim et al. (1975, 1977) claimed that testicular sterilization 
could be achieved in rats by an ultrasound exposure of 1-2 W/cm2 
(apparently at 1.1 MHz) and that, from the evidence of parallel 
experiments with heating applied by other means, the ultrasonic 
action was not purely thermal in nature.  These authors further 
reported that there were no genetic abnormalities in the progeny of 
treated animals in which reduced fertility was observed. 

6.4.4.3.  Summary

    It is not known if ultrasound, under the exposure conditions 
used in diagnostics or therapy, can induce genetic effects. 
Hereditary changes have been observed in cells exposed to 

diagnostic intensities  in vitro and, though the results cannot be 
extrapolated to the  in vivo situation, they do suggest the need 
for further  in vivo investigations. 

    At present, there seems to be little evidence that ultrasound 
produces mutations or chromosomal aberrations in mammalian cells. 
The best evidence of a possible genetic effect is presented by the 
transformation and SCE data, which do not by themselves prove 
genetic damage, but suggest it.  The possible role of cavitation in 
producing effects in cell suspension systems and the relevance of 
cavitation under  in vivo conditions must also be considered. 

6.4.5.  Effects on the central nervous system and sensory organs

6.4.5.1.  Morphological effects

    While large numbers of studies have reported the production of 
lesions in the central nervous system (CNS) following exposure to 
short pulses of very high intensity focused ultrasound, most were 
considered inappropriate for determining health risk assessment and 
have therefore been omitted. 

    Borrelli et al. (1981) reported altered morphology of the 
synapses following exposure of cat brain to pulsed 1 MHz ultrasound 
at an SPTP intensity of 300 W/cm2 for 0.5-3 s.  The authors suggested 
that the morphological changes in the synapses might explain the 
irreversible interruption in CNS function.  They also suggested 
that the synapses may be more sensitive to ultrasonic exposure than 
mitochondria, which have previously been thought to be among the 
structures most sensitive to damage by ultrasound. 

6.4.5.2.  Functional effects

    Hu & Ulrich (1976) exposed the brains of squirrel monkeys to 
2.5-5 MHz ultrasound at intensities ranging from 3 mW/cm2 to 0.9 
W/cm2, and recorded induced potentials using electroencephalograph 
(EEG) electrodes that had been implanted within the brain for long 
periods.  The monkeys were found to adapt to the exposure within 3 
min in that the evoked potentials disappeared, even though the cw 
or pulsed sonication was maintained.  Amin et al. (1981), in an 
investigation similar to that of Hu & Ulrich (1976), did not 
observe any effect on the mammalian EEG during exposure to pulsed 
ultrasound.  They suggested that one possibility for the differences 
was that the 17 Hz and 35 Hz spectral lines observed by Hu & Ulrich 
were harmonics of the signal.  However, this explanation raises a 
question as to why other harmonics were not also seen.  In addition, 
it would not explain why the potentials detected by Hu & Ulrich 
disappeared after 2-3 min of exposure, though the ultrasound 
exposure continued. 

    Changes in microphonic potentials of cats' ears were reported 
following irradiation of the labyrinth of the inner ear through the 
round window of their ears, with 3 MHz ultrasound (200 and 600 
mW/cm2 for 1-5 min) (Molinari, 1968a).  Molinari (1968b) also noted 
that these effects were reversible at the lower intensity but were 

irreversible at the higher intensity, since damage to the neuro-
epithelium of the organ of Corti had occurred. 

    In studies by Farmer (1968), the conduction velocity of human 
axons increased following a 5-min exposure to cw 870 kHz ultrasound 
at a SATA intensity of either 0.5 or 3 W/cm2, but decreased at a 
SATA intensity of 1-2 W/cm2.  The low intensity result (0.5 W/cm2) 
was confirmed by Esmat (1975), but he was unable to confirm the 
findings at the higher intensities.  He proposed that the observed 
changes resulted from temperature elevation.  Using pain sensation 
in the human hand and arm as an end-point, Gavrilov et al. (1976, 
1977) found a wide range of intensity thresholds, depending on 
frequency (0.9-2.7 MHz) and pulse duration (1-100 Ás). 

    Stolzenberg et al. (1980c) reported hindleg dysfunction and 
distended bladder syndrome following exposure of pregnant mice to 
cw 2 MHz ultrasound at a SATA intensity of 1 W/cm2 for 80-200 s. 
This demonstrated that both the autonomic and somatic nervous 
systems were damaged, indicating that prudence is necessary in 
choosing the site of application and duration of therapeutic 
ultrasound treatment.  Another reported functional change in the 
mammalian CNS is the reversible suppression of nerve potentials 
(Fry et al., 1958). 

6.4.5.3.  Auditory sensations

    Gavrilov et al. (1975) noted that pulses of focused ultrasound 
stimulated the auditory receptors of the labyrinth of a frog.  They 
detected bioelectric potentials in the auditory part of the midbrain 
resembling those induced by audible stimuli.  Irradiation of the 
cochlea of human volunteers with 2 MHz focused ultrasound (SPTP 
intensities 50-200 W/cm2, pulse duration 1 Ás) induced click type 
auditory sensations.  The subjects apparently experienced a hearing 
sensation similar to that found in subjects exposed to pulsed 
microwave radiation at power densities of approximately 1 mW/cm2. 
In this case, the auditory sensations or clicks had been shown to 
be due to very localized, minute temperature increases.  A similar 
indirect mechanism could exist for ultrasound, or the effect may be 
due to a direct response to the pulse pressure. 

6.4.5.4.  Mammalian behaviour

    Abnormal behavioural effects in adults may often be caused 
by damage to the CNS at an early stage of development  in utero. 
Physically restrained pregnant rats were exposed to cw 2.3 MHz 
ultrasound at a SATA intensity of 20 mW/cm2 for 5 h on the 9th day 
of gestation, and their progeny investigated immediately after 
birth and 100 days later (Murai et al., 1975a,b).  A delay in 
maturation of the grasp reflex was observed (Murai et al., 1975a). 
Murai et al. (1975b) tested the same animals at 120 days of age and 
found that vocalization to handling and escape response from 
electric foot shock (emotional behaviour) were significantly 
increased in exposed versus sham and untreated control animals.  
It was concluded that the emotional behaviour of rats could be 
influenced by prenatal exposure to ultrasound intensities as low 
as 20 mW/cm2. 

    Altered postnatal behavioural changes were also reported by 
Sikov et al. (1977a), who exposed pregnant rats to cw 0.93 MHz 
ultrasound at SATA intensities of 10-100 mW/cm2, for 5 min, on the 
15th day of gestation.  Similar behavioural abnormalities were 
reported for the righting reflex, head lift, and holding responses. 
The authors concluded that the threshold for these postnatal 
effects must be less than 10 mW/cm2.  However, it was observed that 
these abnormalities were only transient delays in maturation, 
relative to normal controls. Brown et al. (1979, 1981) have not 
been able to repeatedly obtain behavioural effects in mice.  These 
data are summarized in Table 15. 

Table 15.  Behavioural effects in rats and mice
-------------------------------------------------------------------
SATA           Total
intensity      exposure  Effect observed              Reference
(mW/cm2)       time    
               (min)
-------------------------------------------------------------------
20       (cw)  300       delayed neuromotor reflex    Murai et al.
                         development (rat)            (1975b)

20       (cw)  300       altered emotional behaviour  Murai et al.
                         (rat)                        (1975a)

50 - 500 (cw)  2 - 3     variable results (mice)      Brown et al.
                                                      (1979, 1981)
-------------------------------------------------------------------

6.4.5.5.  The eye

    The lens appears to be the part of the eye that is most 
susceptible to ultrasound, because it does not have a blood supply 
to dissipate heat.  A temperature rise above a certain threshold in 
the lens or cornea results in the formation of opaque regions or 
cataracts.  A number of reports (Preisova et al., 1965; Bernat et 
al., 1966a,b; Gavrilov et al., 1974; Zatulina & Aristarkhova, 
1974; Moiseeva & Gavrilov, 1977; Marmur & Plevinskis, 1978) suggest 
mechanisms whereby ultrasound could induce cataracts. 

    Preisova et al. (1965) found that cw 800 kHz ultrasound exposure 
of the eyes of rabbits, for 2 min at SATA intensities greater than 
0.5 W/cm2, caused significant changes in the temperature of the 
cornea.  Pulsed diagnostic ultrasound lasting up to 8 min caused a 
very small increase (0.75 ░C) in the temperature of the eye.  
Zatulina & Aristarkhova (1974) also used pulsed ultrasound (880 
kHz, pulse duration 10 ms, SATA intensities 0.2-0.4 W/cm2) and 
observed alterations in the corneal epithelium, which developed at 
a later date than those resulting from cw exposure at the same 
frequencies and intensities. 

    Lizzi et al. (1978a,b) reported that 2 types of cataracts 
could be induced in the lens of the rabbit eye using high SPTA 
intensities (200-2000 W/cm2) of focused 9.8 MHz ultrasound.  
One was a "haze" cataract, discernible only with slit lamp 

visualization, and the other a totally opaque cataract, occurring 
after long exposure times (i.e., after more energy had been 
deposited).  Fig. 7 presents the total amount of energy deposited 
as a function of the length of exposure necessary to produce a 
minimum detectable haze cataract.  Exposures shorter than 0.1 s 
required a constant energy deposition, whereas longer exposures 
required increasing energy input.  This can be interpreted in terms 
of a thermal mechanism, whereby heat does not have time to diffuse 
away from the site of deposition in a time shorter than 0.1 s.  
With times longer than 0.1 s, more energy has to be supplied to 
allow for heat diffusion out of the focal volume.  The shape of the 
threshold curve obtained seems to be consistent with that predicted 
for thermally-mediated damage (Lerner et al., 1973). 

FIGURE 7

    Using the same focused experimental system, Lizzi et al. 
(1978a) also observed ultrasonically-induced lesions in the retina, 
choroid, and sclera.  The amount of energy required to produce a 
detectable lesion in these parts of the eye was less than that 
needed to generate cataracts in the lens or cornea.  Nevertheless, 
a threshold curve of similar shape was obtained, which was 
compatible with the thermal dissipation characteristics of these 
structures. 

    A specialized low-frequency, ultrasonic, surgical technique 
(phacoemulsification) has been developed for the break-up and 
removal of cataractous lenses.  The phacoemulsifier consists of a 
hollow metal probe oscillating with displacement amplitudes of the 
order of tens of micrometres and frequencies in the range 20-40 
kHz.  Damage to the endothelial cells of the cornea has been 
reported as an undesirable side-effect of the phacoemulsification 
procedure (Talbot et al., l980).  Considerable controversy exists 
as to whether or not this damage is the result of ultrasound action 
or is the result of other non-acoustic factors associated with the 
surgical procedure. 

6.4.5.6.  Summary

    In summary, it can be said that the results of functional 
studies are often contradictory, with electrophysiological 
measurements showing both increases and decreases.  Because of 
experimental differences, and dosimetric uncertainties, the only 
conclusion that can be reached is that cw power densities as low as 
0.5 W/cm2 can induce transient alterations in neural function. 

    Hindleg paralysis and distended bladder syndrome have been 
reported in rodents following exposure to typical therapeutic 
intensities of ultrasound.  Though the small dimensions of the 
rodents would tend to maximize thermal damage, these observations 
indicate that the site of application and duration of exposure of 
therapeutic ultrasound should be chosen with care. 

    Postnatal behavioural effects have been observed in rats after 
exposure to 20 mW/cm2 of cw 2.3 MHz ultrasound as presented in 
Table 15.  If confirmed, the results of postnatal functional tests 
present a serious challenge to the assumption that fetal exposure 
to ultrasound is innocuous. 

    The eye has been identified as an organ sensitive to ultrasound 
exposure.  Ultrasonically-induced lesions occur in the retina, 
choroid and sclera.  The lens of the eye is sensitive to cataract 
production, probably via a thermal mechanism. 

6.4.6.  Skeletal and soft tissue effects

    A number of skeletal and soft tissue effects have been reported 
following exposure to ultrasound.  Many investigations have been 
conducted in this area but, because of the use of ultrasound in 
physiotherapy, only a few representative examples have been chosen 
to illustrate the diversity of the observed effects. 

6.4.6.1.  Bone and skeletal tissue

    It has been common practice in physiotherapy to treat the 
stumps of amputated limbs with high intensities of therapeutic 
ultrasound, to prevent formation of calcified spur growths from 
the cut surface of the bone.  Unfortunately, there are no known 
clinical trials to indicate the efficacy of this therapeutic 
practice, but Kolar et al. (1965) reported that many Eastern 
European publications have indicated reduced skeletal growth in 
dogs, after exposure to ultrasound intensities between 3 and 4 
W/cm2.  In their own studies, Kolar et al. (1965) used a 
magnetostrictive ultrasound source (used in dentistry), with an 
irradiating area of 1.0 cm2, to deliver static exposure to the 
knees of young rats for 5 min.  A significantly reduced calcium 
metabolism was observed, at various times, up to 102 days after the 
exposure, by means of radioisotope tracers. 

    Barth & Wachsmann (1949) found that young dog bones exposed to 
ultrasound levels of 0.5-1 W/cm2 from a stationary transducer 
showed thickening, followed by loss of the periosteum.  Old bones 

showed similar effects, but they took longer to develop.  The 
authors reported that, for a moving ultrasound field, the threshold 
limit for bone damage was about 3 W/cm2. 

    After fracture of the third metatarsal in rabbits, the 
fractures were exposed to ultrasound intensities of at least 0.4 
W/cm2.  The treatment commenced on the third day, for 8 min daily, 
with up to 15 treatments.  X-ray examinations were used to determine 
the differences between the control and sonicated group on the 
tenth day after fracture.  Based on histological examination, it 
was reported that small doses of ultrasound enhanced the process of 
regeneration, differentiation, and resorption of bone tissue.  The 
fracture was reported to weaken within 10-12 days of cessation of 
treatment.  After 45 days, no differences in the healing of 
fractures were observed between experimental and control animals 
(Goldblat, 1969). 

6.4.6.2.  Tissue regeneration - therapeutic effects

    Dyson et al. (1968) reported that tissue regeneration was 
stimulated by low therapeutic intensities of pulsed and cw 
ultrasound.  They measured the rate of repair of symmetrical 1 cm2 
wounds made in both ears of rabbits.  In each animal, the healing 
process in the wound in the unexposed ear was compared with that in 
the ear exposed to ultrasound.  The 3.6 MHz source used by Dyson et 
al. (1968) was described by Pond & Dyson (1967).  Each treatment 
involved a 5-min exposure, with 3 treatments given each week.  The 
intensity that stimulated growth was either 100 mW/cm2 for the cw 
exposures or in the range 0.25-1 W/cm2 (peak) for the pulsed 
exposures (2 ms on and 8 ms off).  The observed regeneration 
rates for the ultrasound-exposed wounds were significantly more 
rapid than those of the unexposed group.  The maximum mean growth 
increase, which was reported to be about 1.3 times that in the 
controls, was found 21 days after treatment at 500 mW/cm2 with 
pulse duration of 2 ms and a pulse repetition rate of 100 Hz.  The 
temperature rise resulting from this exposure was 1.5 ░C.  Because 
of the low intensity at which this effect was observed and the 
small temperature rise, it was attributed to a mechanism other than 
heating (Dyson et al., 1968, 1970; Lehmann & Guy, 1972). 

    Dyson et al. (1976) also investigated the stimulatory effect of 
ultrasound in healing varicose ulcers in human subjects.  The 
ultrasound reduced the ulcer area by about 27% compared with 
untreated controls, 20 days after commencement of treatment.  The 
authors suggested that non-thermal mechanisms might be involved in 
the action of ultrasound on tissues. 

    Goralcuk & Kosik (1976) reported that when rabbits with 
 Staphylococcus aureus-induced suppurative ulcers of the cornea 
were treated with ten, 5-min sessions of 1.625 MHz ultrasound at an 
intensity of 0.4 W/cm2, plus penicillin, better regeneration of 
tissue occurred than with penicillin alone.  Franklin et al. (1977) 
irradiated dog hearts, which had myocardial infarcts, with ultra-
sound (cw 870 kHz, SATA intensity 1 W/cm2 for 10 min) 3 times a 
day for 6 weeks.  There was less dense collagen scarring in the 

treated animals, and the infarcted areas, identified by gross and 
histological examination, were usually smaller in the treated 
animals. 

    In general, there are no clinical trials to support the 
widespread use of ultrasound in physiotherapy (Roman, 1960). 
However, experienced physiotherapists claim that ultrasound is 
efficacious in the treatment of many diverse conditions, e.g., in 
increasing the range of movement at joints.  In support of this 
practice, Gersten (1955) reported increased extensibility of frog 
tendon following a 3-min exposure to pulsed 1 MHz ultrasound (SATA 
intensity approximately 3 W/cm2, pulse duration 1 ms).  The higher 
absorption coefficient of tendon (collagen) relative to other soft 
tissues means that this tissue is selectively heated by ultrasound, 
which may be the underlying mechanism responsible for its apparently 
beneficial effects (Lehmann & Guy, 1972; Lehmann et al., 1978). 

6.4.6.3.  Muscle

    A change in the spontaneous contractile activity of mammalian 
smooth muscle was reported by Talbert (1975), following exposure to 
cw 280 kHz ultrasound at an SATA intensity of 1 W/cm2, but not 
following exposure to 2 MHz ultrasound.  Similar contractions, using 
the same exposure condit ions, have also been found in mouse uterine
muscle  in vivo (ter Haar et al., 1978). 

    Hu et al. (1978) studied the effects of ultrasound on the 
smooth muscle of the rat intestine and found that an intensity of 
1.5 W/cm2 for 5 min at a frequency of 1 MHz inhibited action 
potentials.  This effect was found to be reversible following a 
single exposure, but multiple exposures resulted in only partial 
recovery. 

    When rat cardiac muscle was exposed  in vitro to cw 1 MHz 
ultrasound (SATA intensity of 2.4 W/cm2) for 10 min, the resting 
tension was altered without a corresponding change in its active 
tension (Mortimer et al., 1978). 

6.4.6.4.  Thyroid

    Changes in organ function have been reported for the thyroid 
following ultrasound exposures in the therapy range, i.e., 1 W/cm2, 
0.8 MHz, 10 min (Slawinski, 1965, 1966).  Such exposures were found 
to result in impaired iodine uptake and, in animals with marked 
thyroid hypofunction, reduced iodothyronine synthesis.  Hrazdira & 
Konecny (1966), who reported similar findings, indicated that 
epithelial cells of the thyroid follicles showed a partial loss in 
ability to concentrate inorganic iodine. 

    Some reports have appeared of whole-body systemic effects of 
ultrasonic irradiation, in both experimental animals and man. 
Sterewa & Belewa-Staikova (1976) irradiated the lower abdomen of 
rats at therapeutic intensities (0.2-1.0 W/cm2) and reported a 
consequent decrease in thyroxin and iodothyroxins in the thyroid. 

6.4.6.5.  Treatment of neoplasia

    There has been a revival of interest in the application of 
ultrasound for the treatment of malignant tissues.  Evidence has 
been presented throughout this section that high-intensity 
ultrasound, either alone or in combination with other physical or 
chemical agents, will kill cells.  Earlier work has been reviewed 
by Rapacholi (1969) and a comprehensive review of this topic has 
also been compiled by Kremkau (1979).  Thus only a brief outline 
will be presented below. 

    When solid tumours were exposed  in vivo to peak focal 
intensities of the order of a kW/cm2 for short exposure times, 
reduced tumour growth rate and volume were observed (Kishi et al., 
1975; Fry et al., 1978).  Similar effects have also been reported 
following tumour hyperthermia using lower intensities (0.5-3 W/cm2, 
cw) for exposure times of up to 45 min (Longo et al., 1975, 1976; 
Marmor et al., 1979). 

    Positive and negative synergistic interactions of ultrasound 
and chemicals (Hahn et al., 1975; Heimburger et al., 1975) or 
X-rays (Woeber, 1965; Shuba et al., 1976; Witcofski & Kremkau, 
1978) have been reported for the treatment of cancerous tissues.  
However, some investigators have reported conflicting results with 
different tumour types treated with the same combination of 
ultrasonic and X-ray treatment (Shuba et al., 1976; Witcofski & 
Kremkau, 1978). 

    It is not known whether ultrasound could induce metastases 
during cancer treatment.  However, Siegel et al. (1979), using 
diagnostic intensities (approx. 0.62 mW/cm2), and Ziskin et al. 
(1980), using average intensities of between 12 mW/cm2 and 50 W/cm2 
(880 kHz-2.5 MHz for 5 min-1 h) found increased cell detachment 
following exposure to ultrasound  in vitro.  Evidence for increased 
detachment  in vivo has not been obtained, although  Smachlo et al. 
(1979) found that ultrasonic treatment of hamster tumours (cw 5 
MHz, SATA intensity 3 W/cm2) for 6-8 min caused a reduction in 
tumour growth, and did not cause an increase in the rate of 
occurrence of metastases. 

6.4.6.6.  Summary                                                   
                                                                    
    The effects of ultrasound exposure on skeletal and soft tissues 
are summarized in Table 16.  The data seem to indicate that:  (a)    
damage or retardation of bone growth can occur at intensities in    
the range 2.5-4.0 W/cm2 from a moving transducer, and that damage  
occurs at lower intensities when the transducer is kept stationary; 
(b) young growing bone appears to be more sensitive to the effects  
of ultrasound than older bone; (c) tissue regeneration appears to   
be enhanced by ultrasound exposures at intensities below 2.0 W/cm2; 
this seems to be the case for both soft tissue and bone; (d) ultra- 
sound at therapeutic intensities can trigger muscle contractions    
and inhibit action potentials; (e) ultrasound at therapeutic        
intensities has also been reported to alter thyroid function; 

(f) ultrasound alone (hyperthermia) or in combination with other        
physical or chemical agents may have an application in the          
treatment of neoplasia.                                             

6.5.  Human Fetal Studies

    In the quantification of adverse health effects in the fetus, 
the main problem is the difficulty of demonstrating a causal 
relationship between exposure to ultrasound and a change in the 
normal incidence of spontaneous abnormalities.  Large groups must be 
investigated to obtain statistically significant epidemiological 
data.  The problem of adequate control groups is controversial and 
hinges mainly on what is considered "adequate" (Silverman, 1973). 

6.5.1.  Fetal abnormalities

    There are several frequently quoted studies that claim to show 
that exposure to ultrasound  in utero does not cause any significant 
abnormalities in the offspring (Bernstein, 1969; Hellman et al., 
1970; Falus et al., 1972; Scheidt et al., 1978).  However, these 
studies can be criticized on several grounds, including the lack of 
a control population and/or inadequate sample size, and exposure 
after the period of major organogenesis; this invalidates their 
conclusions as Scheidt et al. (1978) acknowledge. 

    However, studies incorporating larger sample sizes also do not 
show any significant differences in the frequency of fetal 
abnormalities (Morahashi & Iizuka, 1977; Lyons & Coggraves, 1979; 
Koh, 1981; Mukubo et al., 1981, 1982).  Nevertheless, a preliminary 
analysis of the birth records of 2135 children, exposed to ultra-
sound  in utero, indicated the possibility of fetal weight reduction 
(Moore et al., 1982).  Although the data were adjusted for several 
confounding factors, not all factors that might affect lower birth-
weight could be taken into account. While this study does not prove 
a cause-effect relationship, it does provide guidance for designing 
further studies. 

6.5.2.  Fetal movement

    David et al. (1975) indicated a significant increase in 
subjectively assessed fetal activity during routine monitoring of 
36 mothers with cw Doppler ultrasound.  This result has not been 
confirmed by either Hertz et al. (1979) or Powell-Phillips & Towell 
(1979). 

6.5.3.  Chromosome abnormalities

    Several studies have been conducted to determine the incidence 
of chromosome abnormalities in lymphocytes from fetal and maternal 
blood exposed to ultrasound  in vivo.  Only negative or inconclusive 
results have been reported (Abdulla et al., 1971; Serr et al., 1971; 
Watts & Stewart, 1972; Ikeuchi et al., 1973). 

Table 16.  Reported central nervous system, skeletal, and soft 
tissue effects
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
1.5     (p)   5          retardation of growth       Pizzarello et 
                         (newt forelimbs)            al. (1975)

1.5     (p)   360        increased GOT levels in     Tsutsumi et 
                         cerebrospinal fluid         al. (1964)
                         (canine CNS)

3       (p)   3          evoked transient EEG        Hu & Ulrich
                         potentials (primate)        (1976)

8.9     (p)   1.6        effect on liver; depress-   Anderson & 
                         ing phagocytosis (mice)     Barrett (1981)

8.9     (p)   5          immunosupressive effect on  Anderson & 
                         spleen (mice)               Barrett (1979)

10      (cw)  days       microcirculation distur-    Yaroniene
                         bances (rabbits and frogs)  (1978)

10      (p)   30         fetal skeletal variations   McClain et 
                         (rat)                       al. (1972)

40      (cw)  300        increase in skeletal        Shoji et al.
                         abnormalities (mice)        (1971)

50      (p)   15         blockage of gastrulation    Sarvazyan et 
                         (frog embryo explants)      al. (1980)

80      (cw)  5          stable cavitation           ter Haar & 
                         (guinea-pig)                Daniels (1981)

100     (cw)  5          wound healing (rabbit)      Dyson et al.
              (repeated                              (1968)
              exposure)

200           1          reversible changes in       Molinari
                         evoked microphonic          (1968a,b)
                         potentials (cat ear)

400     (cw)  10         healing  of corneal         Goralcuk &
              (repeated  ulcers (rabbit)             Kosik (1976)
              exposure)                                  

500     (cw)  2          haemorrhaging in bone       Bender et 
                         marrow (dog)                al. (1954)       
-------------------------------------------------------------------

Table 16.  (contd.)
-------------------------------------------------------------------
SATA          Total
intensity     exposure   Effect observed             Reference
(mW/cm2)      time
              (min)
-------------------------------------------------------------------
500     (cw)  10         change in thyroid function  Slawinski
                         (guinea-pig)                (1966)

500     (cw)  -          blood stasis (chick)        Dyson & Pond
                                                     (1973)

500     (cw)  10         decrease in SH groups       Chorazak & 
                         (mouse epidermis)           Konecki (1966)

600     (p)   5          fetal skeletal              Hara et al.
                         abnormalities (mice)        (1977), Hara,
                                                     (1980)

500-    (cw)  -          bone thickening and loss    Barth & 
1000                     of periosteum (dog)         Wachsmann 
                                                     (1949)

1000    (cw)  1.3        hindleg dysfunction         Stolzenberg et 
                         (mouse)                     al. (1980c)

1000    (cw)  1.3        distended bladder (mouse)   Stolzenberg et 
                                                     al. (1980c)

1500    (cw)  -          tissue damage (stationary   Hug & Pape
                         transducer) (dog)           (1954)

1000-   (cw)  -          tissue damage (stationary   Lehmann
2000                     transducer) (dog)           (1965b)

2000    (cw)  5          fetal skeletal variations   Hara et al.
                         (mice)                      (1977, 1980)

2400    (cw)  10         change in resting cardiac   Mortimer et 
                         muscle tension (rat)        al. (1978)

2500    (cw)  10         damage to bone marrow       Payton et al.
              (repeated  (dog)                       (1975)
              exposure)

3000    (cw)  5          bone damage (moving sound   Kolar et al.
                         field) (dog)                (1965)

4000    (cw)  -          tissue damage (moving       Lehmann
                         transducer) (dog)           (1965b)

300 000 (p)   0.5-3 s    altered synapse             Borrelli et 
(SPTP)                   morphology (cat)            al. (1981)
-------------------------------------------------------------------

6.5.4.  Summary

    There are many gaps in the data from human studies that 
prevent a meaningful risk assessment of ultrasonic exposure.  
It is therefore necessary to use the results of animal studies to 
test the hypothesis that similar effects may also occur in human 
subjects. Animal studies suggest that neurological, behavioural, 
developmental, immunological, haematological changes and reduced 
fetal weight can result from exposure to ultrasound. 

    Choosing end-points for study is especially difficult in human 
subjects.  Latent periods, before abnormalities become evident, 
could easily be as long as 20 years, or effects may not be seen for 
another generation.  Many human epidemiological studies have 
concentrated on the gross developmental abnormalities evident 
immediately after birth and have yielded negative results with 
various degrees of statistical confidence.  However, a recent human 
study has indicated a tendency towards reduced birthweight 
following ultrasonic diagnostic examination during the course of 
pregnancy (Moore et al., l982). 

    It must be realized that not all possible adverse effects have 
been explored in animal studies and that some potential problems 
that could occur in man may not be revealed in animal studies. 
Another difficulty is that the present understanding of the 
physical mechanisms of interaction of ultrasound with biological 
tissue is inadequate and effects obtained following cw exposures 
cannot be extrapolated to predict the consequences of high-peak 
pulsed exposures at equivalent SATA intensities (or vice versa). 

7.  EFFECTS OF AIRBORNE ULTRASOUND ON BIOLOGICAL SYSTEMS

    Ultrasound devices are routinely used in a wide variety of 
industrial processes, including cleaning, drilling, soldering, 
emulsification, and mixing, as indicated in section 5.  Most of 
these emit airborne ultrasound, not only at the operating 
frequency, but also at its harmonics.  In addition, audible sound 
is often emitted.  Processes such as washing, mixing, and cleaning 
are generally carried out using high ultrasonic intensities that 
cause cavitation.  This can be seen as a type of boiling in the 
liquid and is responsible for the emission of high audible noise 
levels. 

    The term "ultrasound sickness" (Davis, 1948), which came into 
use in the 1940s, included such symptoms as nausea, vomiting, 
excessive fatigue, headache, and disturbance of neuromuscular 
coordination.  No systematic research into the effects of ultra-
sound was conducted until the late 1950s (Gorslikov et al., 1965). 
Since that time a few investigators have studied the effects of 
airborne ultrasound above 10 kHz.  Investigations in the laboratory, 
and in the industrial and general population environments, have 
shown that the possible effects of airborne ultrasound can be 
grouped under four headings:  auditory, physiological, heating of 
skin and tissues, and symptomatic effects. 

7.1.  Auditory Effects

    Since the ear is a sound-sensitive organ, much of the research 
conducted to date has been based on the likelihood that a physical 
hazard resulting from airborne ultrasound will involve the ear and 
may result in a measurable effect on hearing sensitivity.  Airborne 
sound or ultrasound is linked with the human body, through the ear, 
with an efficiency that is 2 or 3 orders of magnitude greater than 
that by any other route. 

    Adverse effects are well documented for exposure to high-
intensity audible sound below 8 kHz and can be measured as 
temporary or permanent threshold shifts (TTS or PTS) in sound 
perception at specific frequencies and sound pressure levels.  
There has been a lack of suitable hearing test equipment and of a 
standard for describing normal hearing above 8 kHz; thus threshold 
shift evaluation above 10 kHz is questionable.  Studies conducted 
to date have relied on control groups that may not have been 
properly selected, thereby introducing bias into the studies.  In a 
report published by Northern et al. (1962), normal hearing thresholds 
were given for frequencies above 8 kHz.  While this study involves 
a small and not very representative sample, it does establish a 
data base that can be used to evaluate data collected in the 
future. 

    Examination of octave band sound pressure levels from ultra-
sonic equipment in the open industrial environment shows equal and 
sometimes greater dB values in the audible range than at ultrasonic 
frequencies.  Ultrasonic frequencies alone have been reported to 
generate audible subharmonics in the ear (Von Gierke, 1950a,b) and 

have been suggested as the cause of auditory effects (Eldridge, 
1950).  Threshold shift studies conducted by Parrack (1966), Acton 
& Carson (1967), Dobroserdov (1967), and Smith (1967) showed mixed 
results.  In studies involving military personnel associated with 
jet aircraft, Davis (1958) could not show any clear auditory or 
non-auditory effects.  Coles & Knight (1965) and Knight & Coles 
(1966) showed that exposure to airborne ultrasound reduced hearing 
sensitivity, but with complete recovery.  In a review of work to 
date, Acton (1973, 1974, 1975) and Acton & Hill (1977) concluded 
that any hazard to hearing from ultrasound frequencies might be due 
to the high-frequency audible components that are usually present 
when airborne ultrasonic fields are encountered. 

    Studies of industrial workers exposed to levels of low-
frequency ultrasound, at approximately 120 dB, failed to reveal 
either temporary or permanent hearing losses (Acton & Carson, 
1967).  However, TTS were noted in the hearing acuity of subjects 
taking part in studies conducted by Parrack (1966).  He noted TTS 
at subharmonics of discrete test frequencies in the range of 17-37 
kHz in subjects exposed for approximately 5 min to 150 dB airborne 
acoustic energy.  It has long been assumed by investigators that a 
TTS is a necessary and sufficient condition (over an extended 
period of time) for a PTS in hearing to occur. 

    A literature search and a field study conducted by Michael et 
al. (1974) is the most comprehensive report published to date on 
the effects of industrial acoustic radiation above 10 kHz. 

7.2.  Physiological Changes

    In studies involving small animals, mild biological changes 
have been reported during prolonged exposure to airborne ultrasound 
with levels in the range of 95-130 dB at frequencies ranging from 
10 to 54 kHz (Acton, 1974).  In studies in man, Asbel (1965) 
reported a drop, and Byalko (1964) an increase, in blood sugar 
levels in workers exposed generally to airborne ultrasound levels 
of more than 110 dB (Asbel, 1965).  An electrolyte imbalance in 
nervous tissues was reported by Angeluscheff (1967), and 
disturbances of sympaticoadrenal activity by Gerasimova (1976). 
Early reports (Asbel, 1965; Angeluscheff, 1967) appear to be 
supported by more recent data (Gerasimova, 1976), where persons 
exposed to noise underwent a stress reaction that induced similar 
effects. 

    Ahrlin & Ohrstrom (1978) reported physiological (non-auditory) 
effects on human beings exposed to acoustic energy above 10 kHz. 

    No significant physiological changes were reported in workers 
as a result of exposure to 110-115 dB at 20 kHz for 1 h (Grigor'eva, 
1966a). 

7.3.  Heating of Skin

    Exposure of mice, rats, and guinea-pigs for about 40 min to 
airborne ultrasound, at sound pressure levels of 150 dB or more, 
results in death due to excessive body heating, and exposure to 
155-158 dB kills the animals in 10 min (Parrack, 1966).  Body 
heating in these animal species was observed at levels exceeding 
144 dB at 18-20 kHz (Allen et al., 1948).  With a hairless strain of 
mice, 155 dB were required to induce the same body-heating (Danner 
et al., 1954).  This result can be explained by the fact that fur 
has a much greater acoustic absorption coefficient than skin 
(Parrack, 1966). 

    In man, exposure to airborne ultrasound at 140-150 dB causes 
vibration of hairs, particularly in the ear canals or nasal 
openings, and a simultaneous local warming at these sites (Parrack, 
1966).  A mild warming of the human body surface may occur at 159 
dB and the lethal exposure of man to airborne ultrasound has been 
calculated to be in excess of 180 dB (Parrack 1966). 

7.4.  Symptomatic Effects

    Some workers exposed to industrial ultrasonic sources such as 
ultrasonic cleaners and drills complained of fatigue, headache, 
nausea, tinnitus, and vomiting (Acton & Carson, 1967; Acton, 1973, 
1974, 1975).  At a sound pressure level of 110 dB, and frequencies 
of 17.6-20kHz, severe auditory and subjective effects, as mentioned 
above, as well as an unpleasant sensation of fullness or pressure 
in the ears were reported by Canadian Forces personnel in the 
vicinity of ultrasonic cleaning tanks (Crabtree & Forshaw, 1977). 
The sound pressure levels did not exceed 105 dB at the operator's 
position (20 kHz one-third octave band) or 95 dB (20 kHz one-third 
octave band) within 4.5 m of the operator. 

    Changes in vestibular function were reported by Knight (1968) 
and Dobroserdov (1967) and may explain the reported feelings of 
nausea.  Possible damage to the vestibular labyrinth is indicated 
in work by Angeluscheff (1954, 1955, 1967).  Many of the reported 
subjective effects occurred at frequencies below 20 kHz and, in 
fact, may occur only in individuals to whom these frequencies are 
audible.  Nausea, dizziness, and fatigue may involve an interaction 
of high-frequency, inaudible sound with cochlear or other inner ear 
functions.  Exposure of man to high sound pressure levels of air-
borne ultrasound causes pressures to be felt in the nasal passage 
or inside the oral cavity when the mouth is open.  Standing wave 
patterns are frequently set up in these areas (Parrack, 1966). 

    The audible components of the airborne acoustic energy 
generated by cavitation in cleaning tanks seem to be directly 
related to subjective complaints, including fatigue and nausea. 
However, these complaints may also be attributed to cleaning 
liquids that have vaporized into the air. 

    Reports that exposure to airborne ultrasound resulted in 
neuromuscular incoordination, loss of ability to do mathematical 
problems, and even complete loss of capacity to perform voluntary 
acts, appear to be without foundation (Brown, 1967). 

7.5.  Summary

    The physiological effects of exposure to airborne acoustic 
energy have been summarized in Fig. 8.  No adverse physiological or 
auditory effects appear to occur in man exposed to sound pressure 
levels up to about 120 dB.  At 140 dB, mild heating may be felt in 
the skin clefts.  With increasing sound pressure levels, the human 
body becomes warmer until death from hyperthermia has been 
estimated to occur at levels greater than 180 dB. 

FIGURE 8

    Subjective or symptomatic complaints such as nausea, vomiting, 
fatigue, headache, and unpleasant sensations of fullness or 
pressure in the ears have been reported by persons exposed in the 
industrial environment.  It is difficult to state that the observed 
effects were due to airborne ultrasound and not audible noise, 
because many sources of exposure contain acoustic frequencies in 
both the audible and ultrasonic range. 

    There is some evidence that any hazard to hearing is probably 
due to the high-frequency audible sound or to subharmonics of the 
ultrasonic frequencies.  However, it has been reported that 
temporary threshold shifts in hearing occur after short exposures 
to airborne ultrasound at 150 dB. 

8.  HEALTH RISK EVALUATION

8.1.  General

    At present, there is insufficient clearly established evidence 
to quantify the health risks resulting from human exposure to 
ultrasound.  In this section, therefore, an attempt is made to put 
the available scientific evidence into perspective, to identify 
possible areas of concern, and also to establish criteria that 
should be satisfied before a meaningful health risk evaluation can 
be performed. 

8.1.1.  Criteria

    A number of criteria, listed in Table 17, must be considered in 
a health risk evaluation of the data on biological effects 
resulting from exposure to ultrasound. 
Table 17. Health risk evaluation criteria for the use of ultrasound:
the principles requiring judgement.
-------------------------------------------------------------------------------
PRIMARY CRITERIA                              WEIGHTING FACTOR

1. Are the data reliable?                      Degree of confidence
2. Does the end point relate to a              Significance of the health risk
    conceivable health risk?
3. Do the exposure-effect data encompass       Degree of coverage of ranges
    the ranges of human exposure
    conditions?
4. Can the data be related to  in vivo          Closeness to  in vivo conditions
    conditions?
5. Are epidemiological data available?         Statistical significance of
                                                findings
6. Is the exposure necessary?                  Benefit expected from exposure
7. Are the physical and biological             Completeness of understanding
    mechanisms understood?

SECONDARY CRITERIA                             WEIGHTING FACTOR

a) Is the exposed organism considered          Degree of sensitivity
    to be especially sensitive?
b) Are the data available from                 Degree of confirmation
    independent sources?
c) Do the data refer to mammalian species?     Closeness to human species
d) Exposure condition?                         Closeness to exposure
                                                condition in human beings
e) Does the exposure occur in combination      Extent of interaction
    with other agents?
-------------------------------------------------------------------------------
These criteria can be applied to the judgement of a particular 
publication or to the body of data relating to a particular end-
point or biological structure.  They are divided into primary 
criteria, which pose questions of a fundamental nature, and 
secondary criteria, which are related to the primary criteria 

and question further details of the studies.  Weighting factors are 
applied to the criteria to provide some quantification and hence to 
assess the relative significance of the biological effects data for 
determining health risks. 

    The following are general examples of how the criteria may be 
applied to various types of studies to determine their significance 
for the evaluation of health risk: 

    i)   In vitro studies on molecules in solution showing
        damage to DNA: though studies of this nature may
        satisfy certain primary criteria, the data cannot be
        extrapolated or related to exposure conditions  in
         vivo and such studies cannot be used for health risk
        evaluation.

    ii)  In vivo exposure of pregnant mice showing effects on
        the offspring:  this type of study may satisfy the
        major primary criteria in demonstrating an effect
        having a significant influence on health risk.  If the
        mechanism is identified as thermal and, as required
        by the secondary criteria, the data have been
        independently confirmed, the health risk evaluation
        revolves around the extrapolation of the ultrasound
        exposure conditions from the mouse to man.  Such an
        evaluation could take the form of the one performed
        by Lele (1975).

    Obviously, judgements must be made about the usefulness of 
experimental data in evaluating health risks.  Although the criteria 
show the questions that must be asked, it is the weighting factors 
that ultimately determine which data indicate the areas of concern. 
Details relating to these areas of concern in various human 
exposure situations are discussed in the following section. 

8.1.2.  Mechanisms

    Most of the effects observed in human beings and experimental 
animals have been attributed to temperature rises resulting from 
the absorption of the ultrasonic energy by tissues (section 3). 
Effects expected to follow such temperature rises are the same as 
those following temperature rises produced by any other agents. 
Tissue heating is the desired intermediate result in most 
physiotherapeutic applications of ultrasound.  In diagnostic 
applications, the rate at which energy is delivered to the tissue 
is usually too low to produce significant heating.  During certain 
types of occupational exposure, tissue heating could occur in 
combination with other stresses. 

    Most of the effects observed when using cells in suspension 
have been attributed to cavitational activity.  Cells suspended in 
a non-absorbing medium are unlikely to be thermally changed, 
because the absorbed acoustic energy, which is converted into heat, 
rapidly diffuses out of the cell (Love & Kremkau, 1980).  Conversely, 
individual cells within tissues all absorb the same amount of heat 
from the acoustic beam, but since there is little net transfer of 
heat out of the cell, a rise in temperature results in the cells as 
well as in the surrounding tissues.  Thus,  in vivo exposures tend 
to maximize thermal effects, whereas the converse applies to  in 
 vitro exposures (Williams, 1982b).  However, ter Haar & Daniels 
(1981) demonstrated that stable gas bubbles (indicative of past 
cavitational activity) were present,  in vivo, in mammalian 
tissues exposed at SATA intensities as low as 80 mW/cm2 (0.75 MHz). 
Also there is evidence of ultrasound-induced effects in blood 
exposed  in vivo, which appear to be the result of cavitation 
(Yaroniene, 1978; Wong & Watmough, 1980).  In this case, the 
exposures were conducted directly over the heart, where turbulent 
rheological conditions may have enhanced nucleation (Williams, 
1982b). 

8.1.3.   In vitro experimentation

    In view of the considerations outlined above, it can be 
appreciated that it is very difficult to extrapolate from an  in 
 vitro to an  in vivo exposure situation.   In vitro experimentation 
allows extensive studies to proceed with reasonable economy of 
resources.  The results of  in vitro experiments are extremely 
valuable for indicating potentially sensitive end-points and 
interaction mechanisms that should be investigated in  in vivo 
studies. 

8.2.  Diagnostic Ultrasound

    Exposure of patients referred for diagnostic ultrasound 
examinations may occur once (if the outcome is negative), 
periodically (for follow-up studies) or intensively for an entire 
day (for fetal monitoring during labour) (section 5.3.1).  Non-
intensive examinations are usually completed within 15-30 min. 

    Long-term occupational exposure of ultrasound technologists and 
sales and service personnel can result from the practice of using 
their own organs as test objects to verify correct functioning and 
desired adjustment of diagnostic ultrasound equipment.  This 
practice should be actively discouraged. Phantom objects are 
available for these purposes. 

    Occupational exposure of the hands of technologists, while 
holding the transducer housing when scanning patients, is 
conceivable but unlikely to be a significant source of risk. 

    The acoustic fields relevant to diagnostic exposures are cw 
fields having space averaged intensities of the order of tens of 
mW/cm2, or pulsed fields having SATA intensities of the order of a 
few mW/cm2 but composed of microsecond pulses, or bursts having 
SPTP intensities that may reach l0-l00 W/cm2. 

    A variety of potentially significant biological effects have 
been demonstrated in cells in suspension (section 6.3.1).  These 
include changes in cell surface properties, alterations in the rate 
of macromolecular synthesis and perturbations in genetic material. 
The interpretation of these results in terms of  in vivo exposures 
is very difficult.  The same effects may not occur within the intact 
organism (when it is subjected to similar exposure parameters), 
because the mechanism of interaction of the cells with the acoustic 
field may be different for the reasons previously described 
(section 8.1.2). 

    A number of reports on small mammals have indicated a decrease 
in the average fetal weight following  in utero exposure to ultra-
sonic intensities that have generally been above the levels commonly 
employed in diagnostic investigations.  It has been proposed that 
high acoustic intensities deposit heat in the fetus, causing a rise 
in temperature which results in the observed effects (Lele, 1975).  
This temperature elevation appears to be less likely to occur in the 
human fetus at typical diagnostic intensities, because of its greater 
size.  However, a similar decrease in fetal weight was observed in 
the mouse fetus under conditions in which a temperature rise was 
considered unlikely (Table l2).  It is also of interest that a 
preliminary analysis of the data on human offspring exposed  in utero 
apparently indicates a statistical association between reduced birth-
weight and ultrasound exposure (Moore et al., 1982).  These findings 
of possible weight reduction deserve further well controlled 
investigation, both experimentally and epidemiologically. 

    Unfortunately, the paucity of data from human studies prevents 
a meaningful risk assessment being made for diagnostic ultrasound 
exposures.  Results of animal studies suggest a wide range of 
potentially significant biological changes, including neurological, 
behavioural, developmental, immunological, and haematological 
effects.  While most of these  in vivo effects are reported to have 
been produced at diagnostic intensities, hardly any have been 
independently confirmed, and in most cases the experimental 
procedures can be criticised on several points.  Bearing in mind 
that not all possible adverse effects have been explored in animal 
studies and that no single effect (with the possible exception of 
fetal weight reduction) is known to be especially sensitive to 
ultrasonic exposure, it is not even possible to predict which 
biological parameters should to be investigated in human 
epidemiological studies. 

    Additional complications in the choice of suitable end-points 
for human studies include:  (i) the long latent period before some 
abnormalities become evident (which could easily be as long as 20 
years in one individual, or perhaps even extend into the next 
generation); and (ii) species-specific effects may occur in man 
that may not be revealed in animal studies. 

8.3.  Therapeutic Ultrasound

    Serial exposure of patients normally occurs in a course of 
physiotherapeutic treatments, typically of 5-20 min duration, 
repeated daily or intermittently for several weeks.  The ultrasound 
source may be applied directly to the skin, using a liquid or gel 
coupling agent, or both the source and limb to be treated may be 
immersed in a water-bath.  In recommended practice, the source is 
moved continuously to distribute the absorbed ultrasonic energy 
throughout the tissue (section 5.3.2). 

    The frequencies used in therapy range from about 1 to 3 MHz and 
the SATA intensities from about 0.1 to 3 W/cm2; the ultrasound is 
applied either in a continuous mode or in pulses that are typically 
1 ms or more in duration. 

    Programmes exist for providing training for physiotherapists 
in the use of ultrasound, and there have not been any clearly 
identified instances of harm to patients from ultrasound applied 
according to recommended procedures.  However, it is easy to cause 
thermal injury (if the source is not moved continuously) when the 
higher intensities are applied.  It is common practice to determine 
the operating intensity by increasing it to a level just below that 
at which the patient experiences pain.  This obviously presents the 
possibility of hazard, if the patient does not possess normal 
sensitivity to pain in the region exposed. 

    Special caution is necessary in physiotherapy when applying 
ultrasound to: 

    (a) bone, particularly growing bone in young children,
        since heating occurs preferentially at the bone surface;

    (b) pregnant women in a manner that might lead to exposure
        of the fetus, because of the possibilities of fetal
        abnormalities caused by temperature elevation;

    (c) the adult or fetal heart, because of the possibilities
        of enhanced cavitational activity.

    Under normal circumstances, occupational exposure of physio-
therapists poses little risk.  However, undesirable exposure of the 
fingers is possible from holding a transducer assembly of faulty 
design or manufacture, or from placing the hands in a water-bath 
being used to treat a patient's extremities.  Some physiotherapists 
deliberately subject themselves to unnecessary ultrasonic exposure 
by routinely using a part of their body (usually the palm of their 
hand) as a biological test object to check that their transducer is 
emitting ultrasound.  This practice ought to be actively discouraged. 

    Information on exposure conditions that lead to changes in 
tissues exposed to ultrasound comes partly from medical experience 
and partly from studies on laboratory animals and other models. 
Possibilities for both harmful and beneficial effects exist in the 
intensity range of therapeutic ultrasound.  There is little evidence 

of therepeutic benefit from the use of SATA intensities of less 
than 0.1 W/cm2 and there does not seem to be any need to use SATA 
intensities greater than about 3 W/cm2.  It is difficult to make a 
clear assessment of risks versus benefits of exposure to therapeutic 
ultrasound, because very few clinical studies have been conducted 
to determine the benefits of the various treatments. 

8.4.  Hyperthermia

    Ultrasound hyperthermia in the treatment of tumours is at 
present only used as an experimental procedure (section 6.4.6.5). 
Absorption of focused ultrasound raises the local tumour 
temperature to 42-44 ░C, causing tumour cell destruction.  The 
upper part (1-3 W/cm2, SATA) of the therapeutic intensity range is 
used, because rapid heating without tissue disruption is desired. 
Exposure occurs typically in serial treatments of up to one hour's 
duration.  Ultrasound offers the advantage of effective energy 
localization for treating deep-seated tumours.  Certain hazards 
obviously attend the procedure. 

    Repeated low-dose hyperthermia can induce thermal tolerance 
(Gerner et al., l976) and possibly stimulate the spread of 
metastases (Dickson & Ellis, l974).  Superficial burns or fat 
necrosis can result from inadequate control of local temperatures. 
The lack of thermal sensors in many deep organs precludes the 
patient from sensing excessive hyperthermia at these sites.  The 
spinal cord and small bowel may be particularly sensitive to heat 
or a combination of heat and radiation, and damage to them may be 
catastrophic (Miller et al., l976b; Merino et al., l978; Luk et 
al., l980).  Metabolic and morphological damage to hepatocytes and 
neurons occurs at 43 ░C (Salcman, l98l).  Despite these hazards, 
hyperthermia treatment has been found to be beneficial for some 
patients who could no longer tolerate or were unresponsive to more 
conventional forms of cancer therapy. 

    Exposure-effect data for ultrasound hyperthermia are sparse and 
subject to considerable uncertainty.  Safety is questionable because 
tumour temperatures must be raised to at least 42.5░C for efficacy, 
while in adjacent normal tissue 45░C must not be exceeded, if 
damage due to protein denaturation is to be avoided. 

    Hyperthermia treatment of tumours requires specialized 
equipment and expertise.  The procedure should not be attempted 
with equipment and facilities intended for physiotherapeutic 
applications. 

8.5.  Dental Devices

    Exposure to ultrasound from dental devices occurs when patients 
have their teeth scaled or cleaned, which typically occurs once or 
twice annually (section 5.3.5).  Adverse effects are quite possible 
when ultrasound devices in dentistry are improperly used.  The 
problem of avoiding such effects should be solved by the application 
of suitable training and operative techniques rather than by 
performing a risk-benefit evaluation, as would be the case in the 
presence of an unavoidable risk. 

    The best known effect is due to heating.  Modern ultrasonic 
scaling devices have a water spray or mist for cooling the tool tip 
and tissue interface.  Since the water mist produced by the nozzle 
obscures vision at the site, optimum water flow adjustment is 
needed (Frost, l977).  Too much water hinders operation and possibly 
drives dislodged calculus into the gingiva; too little leads to 
tip heating and patient discomfort.  It is also necessary that the 
instrument tip be kept in constant motion to avoid unnecessary 
"spot" heating of the teeth (Johnson & Wilson, l957). 

    Scratching or "gouging" of teeth by ultrasound scalers can 
occur if the tool is applied with too much pressure or insufficient 
water is used to provide good coupling (Johnson & Wilson 1957; 
Moskow & Bressman, 1964; Forrest, l967; Wilkinson & Maybury, l973). 
The level of training and experience of the operator are significant 
factors in the type of results obtained with ultrasonic scaling. 
For example, at the beginning of a training course for dental 
hygienists, nearly all the surfaces of the artificial teeth scaled 
showed "considerable scratching" whether scaled by hand or by the 
ultrasound procedure.  Towards the end of a 1-year course, teeth 
showed little or no evidence of this scratching (Forrest, 1967). 

    These devices typically operate at frequencies in the range 
of 20-40 kHz and the tip of the workpiece can be driven with 
displacement amplitudes as high as 40 Ám.  The large impedance 
mismatch between the metal probe and the cooling water, and the 
intermittent nature of the contact between the probe and the enamel 
surface of the tooth, ensure that most of the acoustic energy is 
reflected back into the transducer.  Nevertheless, a significant 
amount of acoustic energy is transmitted through the treated tooth 
and may be conducted through the bones of the upper jaw to the 
inner ear labyrinth where it may adversely affect the patient's 
hearing (M÷ller et al., 1976).  Damage to the hearing of both the 
patient and the operator may also result from airborne ultrasonic 
energy and from high levels of airborne audible sound generated by 
the cavitational activity occurring within the cooling liquid. 

    Occupational exposure through direct coupling of the dental 
hygienist and the applicator is conceivable but of minor concern 
because of the design of the applicators. 

8.6.  Airborne Ultrasound

    Exposure occurs in a variety of occupational and domestic 
settings, e.g., in the vicinity of ultrasonic equipment for 
cleaning, welding, machining, soldering, emulsifying, drying, 
guidance of the blind and robots, intruder detection, TV channel 
selectors, and animal scarers.  Occupational exposure is likely to 
be continuous, while domestic exposure is usually intermittent and 
infrequent. 

    The use of experimental animals to test for biological effects 
has serious drawbacks because, compared with human beings, they 
have a greater hearing acuity, wider audible frequency range, and a 
greater surface-area-to-mass ratio combined with a lower total body 

mass. Most also have fur-covered bodies.  Hence, extrapolation of 
data from airborne ultrasound studies with animals to man cannot 
seriously be considered, except in the most general concepts. 

    In human studies, the hearing acuity of the test and control 
populations must be considered at exposure frequencies where 
perception may be audible, audible with recruitment, or inaudible. 
Recruitment means that the sensation of loudness grows more 
rapidly than normal, as a function of intensity.  Environmental, 
physiological, and psychological factors that may influence the 
number of effects observed must also be considered. 

    There is evidence suggesting that a distinction should be made 
between inaudible airborne acoustic radiation and that containing 
audible components (section 7.1).  In a study in the USSR, 
Dobroserdov (1967) concluded that the "effect produced by high-
frequency sound was more pronounced than that of the ultrasonic 
waves".  Acton & Carson (1967) suggested that "when these effects 
occur, they are probably caused by high sound levels at the upper 
audio frequencies present with the ultrasonic noise".  Several 
other papers report data that indicate the importance of audible 
components (Skillern, 1965; Acton, 1968).  It has also been 
suggested that the ear, when subjected to high levels of inaudible 
ultrasound, may generate subharmonics within the audible range and 
that these subharmonics may be related to some of the observed 
effects (Eldridge, l950; Von Gierke, l950a,b).  Thus, it is 
essential to distinguish the presence or absence of audible 
components in a given exposure to high-frequency airborne acoustic 
radiation. 

8.7.  Concluding Remarks

    (a) The levels of human exposure to ultrasound occurring
        in diagnostic, therapeutic, and dental applications and
        through airborne ultrasound have been indicated in sections
        8.2-8.6. The types of potentially adverse health effects
        likely to require the setting of limits for safe use, or to
        require priority in any risk-benefit decisions, have been
        described.  The lowest levels of exposure in  in vitro, and
        experimental animal studies that resulted in quantitative or
        qualitative biological effects have also been provided,
        together with the results of some preliminary or small-scale
        epidemiological surveys on patients after exposure to
        diagnostic ultrasound.  For each of these applications, an
        attempt has been made to evaluate the existing level of 
        safety or risk.  The degree of uncertainty in these 
        evaluations (because of the unavoidable limitations of 
        present knowledge) has been indicated.

    (b) There are many deficiencies and gaps in the current
        data base for ultrasound-induced bioeffects.  Most of the 
        data apply to mammals other than man, and it is not usually 
        clear how to relate them to human beings.  More information 
        is needed:  (i) on the relationship between degrees of risk 
        posed by peak intensities compared with average intensities; 
        (ii) the possibility of cumulative effects; and (iii) the
        possibility of long-term effects.  Also, very few of the 
        data, either positive or negative, have been verified by 
        other than the original reporter.  Because of the many 
        difficulties associated with work in the area of ultrasound 
        bioeffects, verification of many more of the data is 
        imperative.  These deficiencies and gaps must be resolved 
        before adequate quantification of the safe levels of 
        diagnostic exposure and of any risk-exposure relationships, 
        which are likely to exist at higher levels of exposure, can 
        be achieved.  Even at the present level of research 
        activity, it will probably be many years before such 
        quantification can become conclusive.  In the meantime, 
        actions and recommendations can and should be taken, based
        on current data.  Recommendations or standards could be
        revised as more data become available.

    (c) Current understanding of the mechanisms of interaction
        of ultrasound with biological tissues suggests that a 
        specific threshold region may exist for each well-defined 
        exposure-response relationship.  However, such threshold 
        regions may vary as the values of physical and biological 
        variables change.  If a threshold region exists for any 
        defined response, then sub-threshold exposure would not 
        evoke such a response or cause damage, even after numerous 
        irradiations.  However, exposure levels exceeding the 
        threshold region must entail a degree of risk.  The 
        practical application of the threshold concept is severely 
        limited by the fact that biological conditions within the 
        living body are subject to large intra-and inter-individual 
        variations.  Thus, thresholds tend to become undetectable 
        under marginally supra-threshold exposure conditions as a 
        consequence of this biological variation.  It is this fact, 
        together with the uncertainty that the thresholds even 
        exist under experimental or clinical conditions, that 
        limits the use of this concept in risk-benefit considerations 
        rather than any conceivable non-existence of thresholds.

    (d) With regard to the "Statement on Mammalian  in vivo
        Ultrasonic Biological Effects" of the American Institute of
        Ultrasound in Medicine (AIUM, l978a), the view is still 
        held that it is an adequate statement of the absence of 
        independently confirmed, significant biological effects in 
        mammalian tissues, when the indicated values of exposure to 
        cw ultrasound are not exceeded.  This statement, together 
        with some of the comments that accompanied the original 
        publication of the statement, is reproduced in Appendix 
        III.  It is clear from these that the statement is a 
        generalization of experimental data for  in vivo mammalian 
        systems.  Furthermore, its scope is limited in that very 
        few systematic studies have been conducted in which 
        mammalian systems have been exposed to repeated short, high-
        intensity pulses characteristic of pulse-echo techniques 
        used in diagnostic ultrasound exposures.  It is intended to 
        be only a statement of current experimental bioeffect 
        knowledge, and not an immediate recommendation for
        working levels that must not be exceeded in medical 
        practice.

9.  PROTECTIVE MEASURES

    The diversity and rapid proliferation of applications of 
devices emitting ultrasound, combined with reports of potentially 
adverse health effects, make the need for developing appropriate 
protective measures increasingly important.  Such measures can 
incorporate safety regulations and guidelines, including the 
development of equipment performance standards and exposure limits. 
In addition to specific protective measures, education in this area 
is very important. 

9.1.  Regulations and Guidelines

    An evaluation of the methods for establishing regulations or 
guidelines is becoming increasingly important in the field of 
ultrasound.  The identification of effects that pose potential 
health risks and the way in which limits of exposure might be set 
in standards relative to the biological effects constitute integral 
parts of this evaluation. 

    A standard is a general term, incorporating both regulations 
and guidelines, and is defined as a set of specifications or rules 
laid down to promote the safety of an individual or group of 
people.  A regulation is normally promulgated under a legal statute 
and is referred to as a mandatory standard.  A guideline does not 
generally have any legal force and is issued for guidance only - in 
other words, it is a voluntary standard.  Standards can specify 
limits of exposure and other safety rules for personal protection, 
and/ or specify details on the performance, construction, design, 
or functioning of a device, or methods of testing its performance. 

    The implementation of standards, which limit exposure to 
ultrasound, is intended to benefit the health of exposed persons 
and to provide a frame of reference for industry.  Such standards 
may be useful in the following ways (Repacholi & Benwell, 1982): 

    (a) Their existence serves as a signal to industry and
        the general population that there is concern about
        ultrasound exposure and that they should become aware
        of the potential hazards.

    (b) They provide goals to be achieved at the planning
        stages by manufacturers of devices and by
        organizations involved in the installation and
        construction of ultrasound facilities.

    (c) Devices or facilities producing ultrasound in excess
        of the specified levels should be identified and
        appropriate remedial action taken.

    (d) They form the basis for safe working practices to
        ensure that workers are not exposed to excessive
        levels of ultrasound.

    Standards that relate to performance or performance testing 
provide manufacturers and users with standardized procedures for 
comparing different makes and models of equipment intended to be 
used for the same general purpose. 

    Safe-use guidelines have a number of advantages over 
regulations: 

    (a) they can be introduced more rapidly;

    (b) they can be modified quickly, if necessary;  and

    (c) they can be specified with more flexibility to adjust
        to changes in technology.

    On the other hand, safe-use guidelines have limitations; 
because they are voluntary, they need not be heeded, though peer 
pressure to conform follows from professional and public education 
on the contents of such guidelines. 

9.2.  Types of Standards for Ultrasound

    To protect the general population, patients, and persons 
occupationally exposed to ultrasound, two types of standard are 
generally promulgated: 

    (1) Emission or performance standards, which refer to
        equipment or devices and may specify emission limits
        from a device, usually at a specified distance.
        Detailed specifications on the design, construction,
        functioning, and performance of the device are
        usually given to ensure that the emission limits are
        not exceeded.  An example is the 3 W/cm2 maximum
        output intensity permitted by the Canadian Ultrasound
        Therapy Device Regulation (Canada, Department of
        National Health and Welfare, 1981).  The 3 W/cm2 limit
        is also proposed in the draft standard of the
        International Electrotechnical Commission (1980b).

    (2) Exposure standards, which apply to personnel
        protection and generally refer to maximum levels that
        should not be exceeded in case of whole or partial
        body exposure.  This type of standard has greater
        applicability to ultrasound as used in industry,
        where, for example, exposure standards may limit the
        intensity of airborne ultrasound in the environment
        of the working place.

    Other types of standards that require specific labelling or 
disclosure of performance data, or that specify methods of testing 
performance, also protect patients indirectly. 

    Standards development should preferably be preceded by the 
preparation of, or reference to, a document that summarizes the 
experimental data gained from exposure of various biological 
systems to ultrasound, the known mechanisms of interactions of 
ultrasound with biological systems, and an assessment of the 
various national and international standards.  Such a criteria 
document can form an important scientific basis for incorporation 
of recommendations, from which the need for exposure limits in 
standards can be determined and justified. 

9.2.1.  Standards for devices

9.2.1.1.  Diagnostic ultrasound

    It has been stated that "with expanding services in ultrasound 
diagnosis, the frequency of human exposure is increasing with the 
potential that the major part of the entire population (of some 
countries) may be exposed" (IRPA, 1977).  The US National Center 
for Devices and Radiological Health, using available data on the 
growth rate of sales of diagnostic ultrasound equipment, forecasts 
that the majority of the children born in the USA after the early 
1980s could be exposed to ultrasound  in utero (Stewart & 
Stratmeyer, 1982). 

    The following are some standards and test methods for 
ultrasound that have been developed and reviewed by Repacholi 
(1981) and Repacholi & Benwell (1982). 

    The International Electrotechnical Commission (IEC) is 
developing standards for ultrasound medical diagnostic equipment 
(IEC, 1980a, 1982). 

    The American Institute of Ultrasound in Medicine (AIUM), 
through its standards committee, has been very active in the 
diagnostic ultrasound field.  The following are examples of 
diagnostic ultrasound standards that exist or are being developed: 

         (i)  100 Millimeter Test Object, including standard
              procedure for its use (AIUM, 1974);

        (ii)  American Institute of Ultrasound in Medicine
              standard on presentation and labelling of
              ultrasound images (AIUM, 1978b);

       (iii)  Standard specification of echoscope sensitivity
              and noise level including recommended practice
              for such measurements (AIUM, 1979);

        (iv)  American Association of Physicists in Medicine
              (AAPM) ultrasound instrument quality control
              procedures (AAPM, 1979);

         (v)  Recommended nomenclature: physics and
              engineering (AIUM, 1980);

        (vi)  Pulse echo ultrasound imaging systems:
              performance tests and criteria (AAPM, 1980);

       (vii)  American Institute of Ultrasound in Medicine
              standard for transducer characterization (AIUM,
              1981);

      (viii)  AIUM-NEMA safety standard for diagnostic
              ultrasound equipment (AIUM-NEMA, 1981).

    The Acoustical Society of America (ASA) and the American 
National Standards Institute (ANSI), through their working group 
S3-54, have undertaken to produce a "performance standard for 
ultrasonic diagnostic equipment in use".  The National Bureau of 
Standards (USA) is developing standards for application in 
medicine, industry, and research (National Bureau of Standards 
(USA), 1973), to be used in connexion with measuring power, 
intensity, and radiation field patterns of ultrasound transducers. 

    In France, the Union Technique de l'ElectricitÚ has produced a 
standard for therapeutic ultrasound devices (Association franšaise 
de Normalisation, 1963).  A standard for diagnostic ultrasound 
devices, which includes specifications on construction, labelling, 
use, and conditions for approval was published in 1982 (Association 
franšaise de Normalisation, 1982). 

    The Japanese Standards Association (JSA) has several industrial 
standards for diagnostic ultrasound devices.  These include A-mode 
(JSA, 1976), manual scanning B-mode (JSA, 1978), fetal Doppler 
(JIS, 1979), M-mode (JIS, 1980), and general performance standards 
(JIS, 1981).  Besides safety requirements on electrical parameters, 
construction, design, and testing procedures, there is a 
recommendation that would limit the SATA intensity for fetal 
Doppler diagnostic equipment to no more than 10 mW/cm2.  For manual 
scanning B-mode devices, the Japanese Standards Association (JSA, 
1978) has many of the same requirements as for A-mode devices, 
except that it recommends that when tested under specified free-
field conditions, the ultrasonic intensity should be less than 10 
mW/cm2 for each probe; while for M-mode units, the SATA intensity 
as specified should be less than 40 mW/cm2 for each probe.  It 
should be noted that, in theory, the SPTA intensity is four times 
greater than the SATA intensity but, in practice, the former 
quantity exceeds the latter by a factor of 2 to 6 (section 2.2.1). 

9.2.1.2.  Therapeutic ultrasound

    Ultrasound has been used since the 1930s in physiotherapy. 
Though the biological mechanisms of ultrasound therapy have not 
received systematic investigation, many standards have been 
developed for therapeutic ultrasound devices.  For example, there 
are both French (Association Franšaise de Normalisation, 1963) and 
Australian standards (Standards Association of Australia, 1969) on 
ultrasonic therapy equipment, which indicate ultrasonic output 
tests and techniques of measurement.  Both Canada and the USA have 
published regulations on ultrasound therapy devices under their 

respective radiation control acts (Canada, Department of National 
Health and Welfare, 1981; US Food and Drug Administration, 1978). 
The International Electrotechnical Commission (IEC) is also 
developing safety requirements for therapy equipment (IEC, 1980b). 

    Standards incorporating accuracy specifications for the 
acoustic output power and intensity and for the timer are needed, 
since these directly affect the amount of exposure received by the 
patient.  The labelling of individual applicators is necessary to 
prevent transducers from being connected to the wrong generator, 
and thereby probably causing significant discrepancies between the 
acoustic output and the dial indication. 

9.2.1.3.  Other equipment performance standards

    Working groups of IEC subcommittees 29D and 62D are considering 
standards for the use of ultrasound in dentistry. 

9.2.2.  Exposure standards

    Exposure to ultrasound can be either through direct contact, a 
coupling medium, or the air (airborne ultrasound).  Limits for 
exposure from each mode should be treated separately. 

9.2.2.1.  Airborne ultrasound

    A number of human-exposure limits for airborne acoustic 
radiation have been proposed and these are summarized in Tables 18 
and 19.  From the results of her studies Grigor'eva concluded:  
"The experiments lead one to believe that airborne ultrasound is 
considerably less hazardous to man in comparison with audible 
sound.  Also bearing in mind the data available in the literature, 
120 dB may be adopted as an acceptable limit for the acoustic 
pressure for airborne ultrasound.  The possibility of raising this 
level should be tested experimentally." (Grigor'eva, 1966a, b).  In 
her work on both audible and inaudible components of airborne 
ultrasound, Grigor'eva did not propose any exposure-time limits for 
her suggested values for acceptable limits of acoustic pressure. 

    Acton (1968) proposed a criterion below which auditory damage 
and/or subjective effects were unlikely to occur as a result of 
human exposure to airborne noise from industrial ultrasonic sources 
over a working day.  He based his criterion on the belief that it 
is the high audible frequencies present in the noise from ultra-
sonic machines, and not the ultrasonic frequencies themselves, that 
are responsible for producing subjective effects.  He extended this 
criterion to produce a tentative estimate for an extension to 
damage risk criteria, giving levels of 110 dB in the one-third 
octave bands centred on 20, 25, and 31.5 kHz.  This extended 
criterion was chosen to cover the possible occurence of:  (a) 
generation of first-order subharmonics of potentially hazardous 
levels in the audible frequency range, and (b) subjective effects 
arising from subharmonic distortion products occuring at and below 
16 kHz.  Acton (1974) reported that additional data obtained for 

industrial exposures confirmed that the levels set in the proposed 
criterion were at approximately the right level, and that there did 
not seem to be any necessity to amend them. 
Table 18.  Exposure limits (dB) for airborne acoustic energy at the 
workplacea
-----------------------------------------------------------------------
                  Sound pressure level within one-third octave band
                             (dB relative to 20 ÁPa)
               --------------------------------------------------------
Mid-frequency  Jpn.                                                   
of one-third   Min.   Acton  USSR   USAF  Dept H&W Sweden ACGIH  IRPA 
octave band    Lab.          St.          Canada                 draft     
(kHz)          (1971) (1975) (1975) (1976)(1980b)  (1978) (1981) (1981)
-----------------------------------------------------------------------
8              90     75                  80              80     80
10             90     75                  80              80     80
12.5           90     75     75     85    80              80     80
16             90     75     85     85    80              80     80
20             110    75     110    85    80       105    105    80
25             110    110    110    85    110      110    110    110
31.5           110    110    110    85    110      115    115    110
40             110    110    110    85    110      115    115    110
50             110           110          110      115    115    110
-----------------------------------------------------------------------
a For total ultrasound exposure exceeding 4 h/day.


Table 19.  Permitted increase in sound pressure levels (SPLs) in Table 
18 at workplaces in the vicinity of ultrasound sources
-----------------------------------------------------------------------
         Total ultrasound Permitted rise Total ultrasound Permitted
         exposure time    in SPL         exposure time    rise in SPL
         (per day)                       (per day)
         --------------------------------------------------------------
USSR St. 1 - 4 h          +6             5 - 15 min       +18
(1975)   1/4 - 1 h        +12            1 - 5  min       +24

Sweden   1 - 4 h          +3
(1978)   0 - 1 h          +9

IRPA     1 - 4 h          +3
(draft)  0 - 1 h          +9
(1981)
-----------------------------------------------------------------------
                                                                  
   Parrack (personal communication, 1969) proposed a criterion for 
a standard having acceptable levels of high-frequency airborne 
sound low enough to:  (a) prevent adverse bioeffects (subjective 
effects), and (b) protect the hearing of persons exposed to noise 
from ultrasonic equipment and machines over a working period of 8 h 
per day (nominally) for 5 or 5 1/2 days each week.  The criterion 
was based on Parrack's experimental findings of temporary threshold 
shifts in hearing levels at subharmonic frequencies for several 

subjects exposed to high frequency sound.  The American Conference 
of Governmental Industrial Hygienists used Parrack's criterion for 
their ultrasound exposure levels (ACGIH, 1981). 

    Ultrasound noise is limited to 85 dB per one-third octave by 
the US Air Force (US Air Force, 1976) for frequencies in the range 
of 12.5-40 kHz. 

    The USSR has maximum sound pressure levels to limit exposure of 
workers in the vicinity of ultrasound sources (USSR State Committee 
for Standards, 1975).  The levels are divided into three frequency 
ranges by one-third octave bands.  The maximum sound pressure level 
for the corresponding geometric frequency mean by one-third octave 
band is 75 dB for 12.5 kHz, 85 dB for 16 kHz, and 110 dB for 20 kHz 
(ILO, 1977).  The levels stated therein may be increased, when the 
total duration of exposure does not exceed 4 h per day, in 
accordance with Table 19. 

    The National Board of Occupational Safety and Health in Sweden 
(Sweden, 1978) has issued directions concerning airborne ultrasound 
exposure in the frequency range of 20-200 kHz.  The levels are also 
divided into 3 frequency ranges by the mid-frequency of the one-
third octave band of 20, 25, and > 31 kHz.  The maximum sound 
pressure levels are given in Table 18 for exposure durations 
exceeding 4 h per day and in Table 19 for exposure times of less 
than 4 h. 

    The Department of National Health and Welfare, Canada, (1980b) 
requires that the one-third octave band levels (lines A and B of 
Fig. 9) be used as the exposure limits for airborne ultrasound, 
because adverse health effects seem to arise from "single 
frequency" components.  One-third octave band filters appear to be 
narrow enough in frequency band width for the required analysis.  
These filters are readily available and can be obtained with flat 
response networks up to higher frequencies.  The 6.3 kHz, one-third 
octave band has been chosen to begin specifying criteria levels, 
because no adverse (subjective) effects have been found below this 
frequency. 

    In Japan, noise levels from ultrasonic welders have been 
regulated at values of less than 90 dB for frequencies of less than 
16 kHz (one-third octave band) and less than 110 dB for frequencies 
higher than 20 kHz (one-third octave band), under the provision of 
a circular of the Japanese Ministry of Labour (Japanese Ministry of 
Labour, 1971).  There are many Japanese automobile factories in 
which more than 100 ultrasonic welders are in operation. 

    The International Radiation Protection Association (IRPA,
1981) has drafted the first international limits for human
exposure to airborne acoustic energy having one-third octave
bands with mid frequencies from 8 to 50 kHz.  Tables 18 and 19
indicate the proposed IRPA limits for occupational exposure.
This proposal is similar to the standards existing in a number
of countries.  The document incorporating the proposal also
contains a scientifically based rationale for the limits.  The

IRPA (IRPA, 1981) has also proposed a set of exposure limits
for exposure of the general population to airborne acoustic
energy.  Table 20 gives the details of this proposal.

FIGURE 9

Table 20.  Limits of continuous exposure of the 
general population to airborne acoustic energya
-----------------------------------------------
Mid-frequency of   SPL within one-third octave                   
one-third octave   (dB re: 20 ÁPa)                               
band (kHz)         Day                   Night                   
---------------------------------------------- 
8                  41                    31                      
10                 42                    32                      
12.5               44                    34                      
16                 46                    36                      
20                 49                    39                      
25                 110                   110                      
31.5               110                   110                      
40                 110                   110                      
50                 110                   110                      
-----------------------------------------------
a From:  IRPA (1981).

9.3.  Specific Protective Measures

9.3.1.  Diagnostic ultrasound

    Reviews of current knowledge on biological effects and 
applications of diagnostic ultrasound (section 5.3.1) suggests 
that: 

    (a)  Ultrasonic output information should be supplied to
        the user.  This information should include total power, 
        SATA intensity, SPTA intensity, SPTP intensity, SPPA 
        intensity, pulse length, and pulse repetition frequency, 
        as applicable.  Criteria for imaging effectiveness should 
        also be developed and disseminated.  Such criteria would 
        help the user evaluate benefit versus risks and aid the 
        user in keeping the output of ultrasonic equipment as low 
        as practicable, consistent with obtaining the necessary 
        diagnostic information.

        Some procedures for making intensity measurements have
        been specified (AIUM-NEMA, 1981).  Manufacturers and users
        should strive to develop meaningful standardized techniques 
        to evaluate imaging effectiveness.

    (b)  Output levels approaching the lower limits of those
         used in therapy should not be employed for diagnostic
         purposes, unless they can be justified on the basis of
         obtaining necessary information not otherwise obtainable.
         Equipment with output levels exceeding the lower limits of
         those used in therapy (i.e., SATA intensities above 100
         mW/cm2) should include instruments for monitoring both
         exposure level and exposure time as recommended in the
         Canadian safe-use guidelines (Canada, Department of 
         National Health and Welfare, 1980a).

    (c)  More information is needed with regard to effects of
         exposure from pulsed units before guidelines concerning 
         SPPA or SPTP intensities can be developed.  There is 
         evidence that diagnostic pulse-echo ultrasound causes 
         biological damage to certain tissues.  This effect 
         apparently is a result of some form of cavitation activity 
         and occurs because of microscopic gas-filled spaces within 
         these tissues.  The damage is closely correlated with the 
         temporal peak intensity rather than the time-averaged 
         value (Carstensen, 1982).

    (d)  In general, equipment should be designed with
         adjustable controls so that the operator can use the 
         minimum acoustic exposure required to image or obtain 
         other information concerning the organ of interest in each 
         patient.  These adjustable controls are especially needed 
         for fetal Doppler equipment because:  (i) fetal monitoring 
         can involve extremely long exposure times (of the order of 
         hours or days when a stationary transducer is strapped to 
         the mother's abdomen); (ii) this application involves 

         direct exposure of the fetus.  It should be noted that it 
         is technically and commercially feasible to build effective 
         fetal Doppler equipment with output levels below SATA 
         intensities of 10 mW/cm2 (JIS, 1979).

    (e)  Diagnostic ultrasound should be used for human
         exposure only when there is a valid medical reason.
         Individuals, especially when pregnant, should not be 
         exposed for commercial demonstration or for routine 
         imaging to produce test images when equipment is being 
         serviced (AAPM, 1975).

    (f)  Quality control and testing programmes to ensure
         equipment performance specifications are met should be 
         adopted by manufacturers and users.  Quality control 
         procedures for maintaining diagnostic ultrasound at a high 
         level of efficiency have been described by Goldstein (1982).

9.3.2.  Therapeutic ultrasound

    The reviews of biological effects (section 6), applications 
(section 5.3.2), and instrumentation (section 4) related to 
therapeutic ultrasound suggest that: 

    (a)  Accuracy specifications for the acoustic output power
         and the timer are needed, because both directly affect the
         dose delivered to the patient;

    (b)  There are arguments for and against setting upper
         limits to the intensity of the beam of an ultrasound 
         therapy device.  It should be remembered that physio-
         therapists want to produce an effect on the region of 
         injury, and they require an appropriate amount of ultra-
         sound energy to achieve this aim.  An upper limit might be 
         construed as a "safe level" for exposure, thus encouraging 
         its use.  Above 3 W/cm2, the heat generated is generally 
         unbearable for most patients; moreover such an intensity 
         has been reported to retard bone growth (Kolar et al., 
         1965).  In addition, cavitation, which may cause significant 
         tissue damage, is increasingly possible at intensities above 
         this level. 

    (c)  (i) Because fetal abnormalities and reduced suckling
         weight have been observed after pregnant mice have been
         exposed at therapeutic intensities, no pregnant patient 
         should receive ultrasound therapy in a way that is likely 
         to expose the fetus directly or indirectly.  At present, 
         it is common to give ultrasound therapy to pregnant 
         patients for lower back pain.  This practice should 
         definitely be discouraged.  (ii) It is not advisable to 
         use ultrasound over the vertebral column, especially 
         following laminectomies, or when any anaesthetized areas 
         are involved.  (iii) Care should be taken when epiphyseal
         lines in children are exposed to ultrasound, especially 
         when these regions are still at the growing stage.  (iv) 

         Care should be exercised, when treating peripheral vascular 
         disease within extremities, because with diminished 
         sensation and lack of blood circulation, the patient may 
         not detect overexposure to ultrasound.

    (d)  Ultrasound exposure close to a strong reflecting
         surface such as bone may lead to the formation of standing
         waves, with the possibility of producing blood-flow stasis 
         and related effects.  Endothelial damage to the blood 
         vessels may ensue, if such stasis occurs for extended 
         periods of time.  In therapy, the ultrasound transducer 
         should be moved over the region of injury to minimize 
         harmful effects from standing waves and possible cavitation.

    (e)  Operators of therapeutic ultrasound devices should
         avoid exposure in two main areas:  (i) large blood pools 
         (e.g., heart, spleen); (ii) reproductive organs (e.g., 
         testes, ovaries, pregnant uterus).

         Most of the precautions listed above are not absolute and
         refer to the direct exposure of the site mentioned.  They 
         are on the conservative side and may change as more data 
         become available.  While there would be a contraindication 
         for therapy with high SATA intensities in a case of 
         peripheral vascular insufficiency in the leg, this would 
         not mean that the same patient could not be treated with 
         ultrasound for a "frozen" shoulder.  Likewise, though the 
         pregnant uterus should not be directly exposed to therapeutic 
         ultrasound, applications to other parts of the body, such 
         as an extremity, should not result in any significant 
         exposure of the fetus. 

    (f)  Patient exposure can and should be minimized by:  (i)
         testing patient skin sensation prior to application of
         ultrasound (if patients have sensory paralysis and are 
         unable to differentiate between hot and cold, an 
         alternative type of treatment should be given, since they 
         would not be able to detect overexposure; the same 
         criterion applies to treating patients when anaesthetised 
         areas are involved); (ii) using the minimum effective 
         exposure (i.e., ultrasound power and duration of exposure); 
         (iii) keeping the energized transducer moving slowly over 
         the treatment region to minimize the risk of "hot spots" 
         (undue temperature elevation in tissue receiving excessive 
         exposure); (iv) reducing the ultrasound power level, if a 
         mild tingling sensation or pain is felt in the treatment 
         region (such a sensation may be an indication that there 
         is overheating within the treatment region, and significant 
         damage to the tissue could occur if this sensation is 
         allowed to continue); (v) ensuring that the operator is
         present to terminate the treatment if the patient shows 
         the least sign of distress; (vi) calibrating equipment 
         used for treatment purposes to provide the operator with 
         the capability of delivering acoustic intensities that are 
         below levels at which adverse biological or subjective 
         effects have been reported. 

    (g)  Well-designed controlled clinical trials should be
         carried out to evaluate the effectiveness of ultrasound
         treatments.  By this means, ineffective treatments may be
         identified and either eliminated or modified so that they
         become efficacious.

    (h)  Operator exposure can be minimized by:  (i) not
         touching the face of the transducer or applicator when it 
         is emitting ultrasound; and (ii) not immersing any part of 
         the operator's body in the water bath while ultrasound is 
         being generated.

9.3.3.  Industrial, liquid-borne, and airborne ultrasound

    The reviews of industrial, liquid-borne, and airborne 
ultrasound sources (section 5.1, 5.2, 7) and effects suggest that: 

    (a)  Exposure levels should be minimized and certainly be
         below levels at which adverse biological or subjective 
         effects have been reported.

    (b)  Persons exposed to high levels of noise associated
         with ultrasonic equipment should be protected either by
         wearing devices such as earmuffs, or by acoustic barriers
         constructed around the equipment to reduce the noise 
         levels.

    (c)  Direct contact exposure to high intensities of
         liquid-borne ultrasound should be avoided.  For example,
         operators should not place their hands in ultrasonic 
         cleaning tanks during operation.  Warning signs to this 
         effect should be placed at suitable locations.

    (d)  In burglar alarm systems, the ultrasonic source
         itself should be switched off, instead of only the alarm, 
         when the system is not in use.

    (e)  Care should be taken that ultrasonic transmitters
         used for smoke coagulation are located so that they do not
         expose workers nearby.

9.3.4.  General population exposure

    The general population may be exposed to ultrasound from a 
number of sources.  Some of these might be grouped as: 

    (a)   Consumer sources, exemplified by ultrasonic cleaners,
         remote control devices, sonar devices, dog control and
         repelling devices, distance-measuring devices for cameras, 
         etc.

    (b)   Public sources, exemplified by sources in public
         areas such as door openers, burglar alarms, devices for 
         bird and rodent control, etc.

    Of the devices mentioned above, only the ultrasonic cleaners, 
dog repelling devices, and burglar alarms are likely to cause any 
concern.  Consumer sources are often handled by a limited number of 
persons, who should obtain pertinent information concerning function, 
use, and possible risks.  Manufacturers should only market devices 
in which the operational intensities are considered safe to use and 
comply with standards current at the time of manufacture (section 
9.2.2.1).  Unnecessary use should be avoided. 

    In addition to these protective measures, ultrasound sources 
used near the general population should be properly labelled with 
appropriate protective information; the radiation area should be 
marked so that people will avoid staying in radiated areas for 
prolonged periods. 

9.4.  Education and Training

    An educational programme on the safe use of ultrasound is one 
of the most important aspects of protection.  Such a programme 
entails education of the general population and training of users 
of ultrasound devices.  The development of educational materials 
should be a key aspect of such a programme. 

    A document outlining safe-use guidelines for device operators 
should include the following: 

    (a) care and use of ultrasound equipment;

    (b) measurement and calibration of the equipment;

    (c) operator training programme;

    (d) a summary of biological effects that may arise from
        ultrasound exposure;

    (e) information on how patient doses can be reduced by
        lowering exposure where practical;

    (f) contraindications - when not to use ultrasound;

    (g) recommended exposure limits;

    (h) safe operating procedures.

    Publications containing such information are available (AAPM, 
1979; Canada, Department of National Health and Welfare, 1980a,b; 
Goldstein, 1982). 

    Many applications of ultrasound involve control of complicated 
equipment.  In diagnostic imaging procedures, for example, the skill 
of the operator has a great influence on the diagnostic efficiency 
on the time required to make the examination.  The operator has to 

select scanning planes and instrument parameters in an interactive 
process dependent on the actual findings.  Incorrect control of the 
ultrasound scanner can result in two different forms of risk: 

    (a) excessive exposure of the patient to ultrasound
        radiation because of long exposure times;

    (b) incorrect diagnosis, which in turn might lead to
        repeated exposures.

    The obvious solution is well-planned and supervised education 
and training of all personnel working with ultrasound radiation. 

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FAHIM, M.S., FAHIM, Z., DER, R., HALL, D.G., & HARMAN, J.
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FARMERY, M.J. & WHITTINGHAM, T.A.  (1978)  A portable
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GREGORY, W.D., MILLER, M.W., CARSTENSEN, E.L., CATALDO, F.L.,
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HAUPT, M., MARTIN, A.O., SIMPSON, J.L., IQBAL, M.A., ELIAS,
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HEIMBURGER, R.F., FRY, F.J., FRANKLIN, T.D., & EGGLESTON,
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HODGSON, W.J.B., BAKARE, S., HARRINGTON, E., FINKELSTEIN, J.,
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HUSTLER, J.E., ZAROD, A.P., & WILLIAMS, A.R.  (1978)
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WILKINSON, R.G. & MAYBURY, J.E. (1973)  Scanning electron
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 J. Periodontol., 44: 559.

WILLIAMS, A.R. (1972)  Disorganization and disruption of
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 J. Acoust. Soc. Am., 52: 688-693.

WILLIAMS, A.R. (1974)  Release of serotonin from human
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WILLIAMS, A.R. (1977)  Intravascular mural thrombi produced by
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WILLIAMS, A.R. & MILLER, D.L.  (1980)  Photometric detection
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WILLIAMS, A.R., HUGHES, D.E., & NYBORG, W.L. (1970) Hemolysis
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WILLIAMS, A.R., O'BRIEN, W.D. Jr, & COLLER, B.S. (1976a)
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WILLIAMS, A.R., SYKES, S.M., & O'BRIEN, W.D. Jr (1976b)
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(1980)  Mammalian multicellular tumor spheroids: An
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ZWEIFEL, H.J.  (1979)  [Relationship between investigator and
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German).

APPENDIX I:  Ultrasonic quantities:  Symbols and units
---------------------------------------------------------------------------
 Quantity                      Symbol       Unit         Other commonly
                                                         used subunit(s)
---------------------------------------------------------------------------
 (Amplitude) Attenuation       alpha        m-1          Np/cm or dB/cm*
  coefficient

 (Amplitude) Absorption        alphaa       m-1          Np/cm or dB/cm*
  coefficient

 Characteristic acoustic        Zo           Pa x s/m
  impedance                    or rho c      or kg/m2s

 Adiabatic bulk modulus         K            Pa

 Angular frequency             omega        rad/s        s-1

 Adiabatic bulk                 B            Pa-1
  compressibility

 Density                       rho          kg/m3        g/cm3

 Energy                         E            J

 Energy density                 W            J/m3

 Force                          F            N

 Frequency                      f            Hz           kHz or MHz

 Intensity:
  Intensity (peak)              Ip           W/m2         W/cm2 or mW/cm2

  Intensity (averaged           Ia           W/m2         W/cm2 or mW/cm2
   over one cycle)

 Spatial peak - temporal       ISPTP        W/m2         W/cm2 or mW/cm2
  peak intensity

 Spatial peak - pulse          ISPPA        W/m2         W/cm2 or mW/cm2
  average intensity
---------------------------------------------------------------------------
*  If alpha = 1 cm-1, then alpha = 1 Np/cm = 8.686 dB/cm

---------------------------------------------------------------------------
 Quantity                      Symbol       Unit         Other commonly
                                                         used subunit(s)
---------------------------------------------------------------------------
 Spatial peak - temporal        ISPTA        W/m2         W/cm2 or mW/cm2
  average intensity

 Spatial average - pulse        ISAPA        W/m2         W/cm2 or mW/cm2
  average intensity

 Spatial average -              ISATA        W/m2         W/cm2 or mW/cm2
  temporal average intensity

 Particle acceleration          a            m/s2

 Particle displacement         xi           m            Ám

 Particle velocity              v            m/s          cm/s

 Power                          P            W

 Pressure                       p            Pa           N/m2

 Speed of sound                 c            m/s

 Coefficient of                eta          Pa x s
  shear viscosity

 Wavelength                    lambda       m            cm, mm
---------------------------------------------------------------------------
Note:   In the units column, m = metre, s = second, kg = kilogram,
        N = newton, Pa = pascal, W = watt, Np = neper, Hz = hertz,
        dB = decibel, J = joule.
    The following relationships between the above parameters apply 
for a continuous monochromatic idealized plane travelling wave 
field in a homogeneous lossless medium. 

Particle displacement
xi = xio sin (omegat - kx)
where xio = displacement amplitude
omega = 2pi f = angular frequency
k = 2pi/lambda = circular wave number
 t = time
 x = propagation distance

Particle velocity
 v = deltaxi /deltat =  vo cos (omegat - kx)
where  vo = deltaxio = velocity amplitude

Particle acceleration
 a = delta v/delta t =  -ao sin (omegat - kx)
where  ao = omega2xio = acceleration amplitude


Acoustic pressure
deltap/deltax = -rho a, hence
 P =  Po cos (omegat - kx)
 Po = rhoomega2xio/k = pressure amplitude
 c = speed of sound

Energy density
The energy density of the sound field is
 W = rho vo2/2 or, using
 Zo = rho c,  vo = omegaxio,  Po = rhoomegaxio
 W = rho Po2/2 Zo2 =  Po2/2rho c2

Intensity
The average intensity (averaged over one cycle
of the wave) is given by
 Ia =  cW;
hence, using  W =  Po2/2rho c2
 Ia =  Po2/2rho c

    For a given intensity, the quantities xio,  vo,  ao,
and  Po can be calculated from
xio = 1/omega(2 Ia/rho c)0.5
 vo = (2 Ia/rho c)0.5
 ao = omega(2 Ia/rho c)0.5
 Po = (2rho cIa)0.5

    The above relationships are based on the assumption of a plane 
continuous (sinusoidal) wave, and  Ia represents the intensity of 
the wave averaged over one cycle.  In such a wave, the instantaneous 
peak intensity ( Ip) is twice the cycle average value ( Ia), i.e.  
 Ip = 2 Ia. 

    Pulse mode therapy units are normally calibrated in terms of 
cycle average intensity.  If the wave consists of short asymmetric 
pulses, such as those emitted by pulse-echo diagnostic ultrasound 
instruments, it is usually not possible to define an average over 
one cycle.  It is therefore necessary to specify the output of such 
instruments in terms of the instantaneous peak intensity ( Ip). 
In Appendix I, Table 1, particle parameters for typical medical 
diagnostic instruments are given in terms of the average intensity 
(therapeutic and cw Doppler instruments) or the peak intensity 
(pulse-echo instruments). 

Appendix I, Table 1.
Particle parameters in an idealized aqueous medium for typical frequencies and 
intensities generated by medical ultrasonic equipmenta
-----------------------------------------------------------------------------------
                 Therapeutic        Diagnostic Ultrasound     Diagnostic Ultrasound
                 Ultrasound         Pulse Echo                cw Doppler
                  Ia = 100-3000       Ia = 100-100 000           Ia = 1-20
                 mW/cm2             mW/cm2                    mW/cm2
                  f = 1.0 MHz (cw)   centre freq.= 2.25 MHz     f = 2.25 MHz (cw)
-----------------------------------------------------------------------------------
Acoustic         5.4 x 104 to       3.8 x 104 to              5.4 x 103 to
pressure         2.9 x 105          1.2 x 106                 2.4 x 104
amplitude
(N/m2)
-----------------------------------------------------------------------------------
Displacement     5.8 x 10-9 to      1.8 x 10-9 to             2.6 x 10-10 to
amplitude        3.2 x 10-8         5.8 x 10-8                1.2 x 10-9
(m)
-----------------------------------------------------------------------------------
Particle         3.7 x 10-2 to      2.6 x 10-2 to             3.7 x 10-3 to
velocity         2.0 x 10-1         8.2 x 10-1                1.6 x 10-2
(m/s)
-----------------------------------------------------------------------------------
Particle         2.3 x 105 to       3.7 x 105 to              5.2 x 104 to
acceleration     1.3 x 106          1.2 x 107                 2.3 x 105
(m/s2)
-----------------------------------------------------------------------------------
a  Displacement amplitude, pressure amplitude and particle velocity are
   calculated from intensities according to relationship for a plane,
   continous monochromotic travelling wave in an idealized aqueous medium.
APPENDIX II:  List of definitions related to the measurement
and calibration of ultrasonic equipment
________________________________________________________________________

AMPLITUDE MODULATION FACTOR: the value of the expression 100 ([A] - 
[B])/([A]) where [A] and [B] are the respective absolute maximum 
and minimum values of the envelope of a modulated acoustic or 
electrical carrier (first-order quantity) expressed as a 
percentage. 

AMPLITUDE-MODULATED WAVEFORM: A waveform in which the
AMPLITUDE MODULATION FACTOR is greater than 5% (see WAVEFORM).

BANDWIDTH: The difference in the frequencies  f1 and  f2 at which 
the transmitted acoustic pressure spectrum is 71% (-3 dB) of its 
maximum value. 

BEAM AXIS: A straight line (calculated according to regression 
rules) joining the points of maximum pressure amplitude in planes 
parallel to the surface of the transducer assembly in the far field 
of the acoustic beam. 

BEAM CROSS-SECTION: The surface in a plane perpendicular to the 
beam axis consisting of all the points at which the intensity is 
greater than x% of the spatial maximum intensity in that plane. For 
beams from therapy equipment, x is usually 5%; for ultrasonic 
fields from diagnostic equipment, x is usually 25%. 

BEAM CROSS-SECTIONAL AREA: The area of the BEAM CROSS-SECTION.

BEAM NON-UNIFORMITY RATIO: The ratio of the value of the temporal 
average intensity at the point in the ultrasonic field where the 
temporal average is a maximum (i.e., the spatial peak temporal 
average intensity) to the spatial average temporal average 
intensity in a specified plane. 

CENTRE FREQUENCY: ( f1 +  f2)/2 where,  f1 and  f2 are 
frequencies as defined in BANDWIDTH.  For an asymmetrical spectrum, 
the frequency at which the spectrum has a maximum is different from 
the centre frequency. 

CONTINUOUS WAVEFORM: A waveform in which the AMPLITUDE MODULATION 
FACTOR is less than or equal to 5% (see WAVEFORM). 

CYCLE AVERAGE INTENSITY ( Ia):  The intensity of the wave average 
over one cycle.  In such a wave the instantaneous peak intensity 
(Ip) is twice the value of  Ia, i.e.  Ip = 2 Ia (see Appendix I). 

DEPTH OF FOCUS:  The distance along the beam axis, for a focusing 
transducer assembly, from the point where the beam cross sectional 
area first becomes equal to 4 times the focal area to the point 
beyond the focal surface where the beam cross-sectional area again 
becomes equal to 4 times the focal area. 

DUTY FACTOR:  The ratio of the PULSE DURATION to the PULSE 
REPETITION PERIOD or the product of the PULSE DURATION and the 
PULSE REPETITION FREQUENCY. 

ENVELOPE:  A waveform which connects the relative maxima on the 
absolute value of the instantaneous acoustic pressure waveform. 

FOCAL AREA:  The area of the FOCAL SURFACE.

FOCAL LENGTH:  The distance along the BEAM AXIS between the points 
at which the BEAM AXIS intersects the surface of the transducer 
assembly and the FOCAL SURFACE. 

FOCAL SURFACE:  The smallest of all BEAM CROSS-SECTIONS of a 
FOCUSING TRANSDUCER. 

FOCUSING TRANSDUCER:  A transducer assembly in which the ratio of 
the smallest of all BEAM CROSS-SECTIONS to the RADIATING CROSS-
SECTIONAL AREA is less than one-fourth. 

FRACTIONAL BANDWIDTH:  BANDWIDTH divided by centre frequency. 

INTENSITY:  The quotient of the instantaneous acoustic power 
transmitted in the direction of acoustic wave propagation, and the 
area normal to this direction, at the point considered.  The term 
should be used with appropriate modifiers such as spatial peak or 
average and temporal peak or average.  For measurement purposes, 
this point is restricted to where it is reasonable to assume that 
ACOUSTIC PRESSURE and particle velocity are in phase; viz, in the 
FAR FIELD or the area of the focus. 

POWER:  (See also ULTRASONIC POWER).  The rate of energy transfer, 
i.e. energy flow divided by time. 

PULSE AVERAGE INTENSITY:  The ratio of the time integral of PULSE 
INTENSITY to the PULSE DURATION. 

PULSE DURATION:  A time interval beginning when the absolute value 
of the acoustic pressure first exceeds x% of the maximum absolute 
value of the acoustic pressure and ending at the last time the 
absolute value of the acoustic pressure returns to this value.  For 
waveforms from therapy equipment, x is usually 10%; for waveforms 
from diagnostic equipment, x may be larger, for example 32% (i.e. 
minus 10 dB). 

PULSE REPETITION FREQUENCY:  The repetition rate of the pulses of a 
pulsed ultrasound beam; the inverse of the PULSE REPETITION PERIOD. 

PULSE REPETITION PERIOD:  The time between corresponding parts in 
the waveform of successive pulses from a transmitter.  The pulse 
repetition period is equal to the reciprocal of the PULSE 
REPETITION FREQUENCY. 

RADIATION CROSS-SECTIONAL AREA:  The BEAM CROSS-SECTIONAL AREA at 
the surface of the transducer assembly. 

SCAN CROSS-SECTIONAL AREA:  For auto-scanning systems, means the 
area on the surface considered, consisting of all points occurring 
within the BEAM CROSS-SECTIONAL AREA of any beam passing through 
the surface during these scans. 

SCAN REPETITION FREQUENCY:  The repetition rate of a complete 
frame, sector or scan.  The term only applies to automatic scanning 
systems. 

SCAN REPETITION PERIOD:  The inverse of the SCAN REPETITION 
FREQUENCY. 

SPATIAL AVERAGE-PULSE AVERAGE (SAPA) INTENSITY:  The PULSE AVERAGE 
INTENSITY averaged over the BEAM CROSS-SECTIONAL AREA. 

SPATIAL AVERAGE-TEMPORAL AVERAGE (SATA) INTENSITY:  For auto-
scanning systems, it is the TEMPORAL AVERAGE INTENSITY averaged 
over the SCAN CROSS-SECTIONAL AREA on a specified surface.  This 
may be approximated as the ratio of ULTRASONIC POWER to the SCAN 
CROSS-SECTIONAL AREA or as the mean value of the ratio if it is not 
the same for each scan.  For non-auto-scanning systems, SATA 
intensity is the TEMPORAL AVERAGE INTENSITY averaged over the BEAM 
CROSS-SECTIONAL AREA (may be approximated as the ratio of 
ULTRASONIC POWER to the BEAM CROSS-SECTIONAL AREA). 

SPATIAL PEAK-PULSE AVERAGE (SPPA) INTENSITY:  The value of the 
PULSE AVERAGE INTENSITY at the point in space where the PULSE 
AVERAGE INTENSITY is a maximum, or is a local maximum within a 
specified region. 

SPATIAL PEAK-TEMPORAL AVERAGE (SPTA) INTENSITY:  The value of the 
TEMPORAL AVERAGE INTENSITY at the point in the acoustic field where 
the temporal average intensity is a maximum, or is a local maximum 
within a specified region. 

SPATIAL PEAK-TEMPORAL PEAK (SPTP) INTENSITY:  The value of the 
TEMPORAL PEAK INTENSITY at the point in the acoustic field where 
the temporal peak intensity is a maximum, or is a local maximum 
within a specified region. 

TEMPORAL AVERAGE INTENSITY:  The time average of intensity at a 
point in space.  For non-auto-scanning systems, the average is 
taken over one or more PULSE REPETITION PERIODS.  For auto-scanning 
systems, the intensity may be averaged over one or more SCAN 
REPETITION PERIODS for a specified operating mode. 

TEMPORAL PEAK INTENSITY:  The peak instantaneous value of the 
intensity at the point considered. 

ULTRASONIC POWER:  Usually, the temporal average power emitted in 
the form of ultrasonic radiation by a transducer assembly. 

WAVEFORM:  The representation of an acoustic or electrical
parameter as a function of time.

APPENDIX III:  Comments prepared by the American Institute of
Ultrasound in Medicine (AIUM) Bioeffects Committee regarding the 
AIUM statement (AIUM, 1978a). 

-------------------------------------------------------------------

Statement

    "In the low megahertz frequency range there have been (as of 
this date) no independently confirmed significant biological 
effects in mammalian tissues exposed to intensities (a*) below 100 
mW/cm2.  Furthermore, for ultrasonic exposure times (b**) less than 
500 seconds and greater than one second, such effects have not been 
demonstrated even at higher intensities, when the product of 
intensity (a) and exposure (b) is less than 50 joules/cm2." 

Comments

    "This Statement apparently applies to all existing data on 
biological changes produced in mammalian tissues by ultrasound in 
the frequency range from about 0.5 to 10 MHz.  Included in our 
literature review leading to this Statement are results obtained 
with focused as well as unfocused ultrasonic fields, generated 
continuously or (to a lesser extent) in a series of repeated 
pulses. 

    "The Statement has included all seemingly reliable data from 
the literature as well as results of satisfactory quality that have 
been published more recently. We have consulted a number of 
informed investigators and have not learned of any exception to the 
Statement.  However, in any application of the Statement to 
decisions concerning the safety of human beings, attention should 
be given to the following considerations: 

1.  Most of the data apply to mammals other than man, and it
    is not clear how to relate them to the human situation.

-------------------------------------------------------------------
 *  (a) Spatial peak, temporal average as measured in a free
     field in water.  The spatial peak intensity should be
     determined with a device, such as a calibrated
     miniature hydrophone, for which the dimensions of the
     sensitive area are smaller than the distance over the
     local value of the ultrasound field intensity shows a
     significant variation.

**  (b) Total time; this includes off-time as well as on-time
     for a repeated pulse regime.

2.  While useful results are now being generated in several
    research laboratories, the pool of reliable and highly
    relevant data is only beginning to fill.  Especially in
    short supply are results at low intensities and long
    exposure times.  Little research has been done with
    repeated short pulses such as would be most relevant to
    diagnostic ultrasound.  Also most experiments have not 
    been repeated by independent investigators.

3.  Data available at present on intensity levels at which
    bioeffects occur are, in general, not minimum levels (if,
    indeed, definite minima exist).  Further research is
    urgently needed to determine whether significant
    biological changes occur at levels lower than those
    corresponding to the Statement.  As more results become
    available, it is reasonable to expect at least some
    lowering of the observed "threshold" levels for some
    biological systems, especially as more sensitive
    biological tests are used, and as more critical physical
    conditions are identified. 

4.  We believe the Statement will be helpful in arriving at
    recommendations for the wise use of ultrasound in
    medicine.  However, the Statement does not, in itself,
    imply specific advice on "safe levels" which might be
    universally valid.  Determination of recommended maximum
    levels will require consideration of such difficult topics
    as: adequacy of present knowledge of bioeffects; expected
    reliability of equipment specifications; assessment of
    patient benefits; and others.  So far these matters have
    not been treated systematically". 




    See Also:
       Toxicological Abbreviations