Ultrasound (EHC 22, 1982)

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

The World Health Organization welcomes requests for permission
to reproduce or translate its publications, in part or in full.
Applications and enquiries should be addressed to the Office of
Publications, World Health Organization, Geneva, Switzerland, which
will be glad to provide the latest information on any changes made
to the text, plans for new editions, and reprints and translations
already available.

^(c) World Health Organization 1982

Publications of the World Health Organization enjoy copyright
protection in accordance with the provisions of Protocol 2 of the
Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material
in this publication do not imply the expression of any opinion
whatsoever on the part of the Secretariat of the World Health
Organization concerning the legal status of any country, territory,
city or area or of its authorities, or concerning the delimitation
of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar
nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished by initial capital
letters.

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 Germany^a

Dr K. Lindström, Department of Biomedical Engineering,
University Hospital, Malmö, 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. Duchêne, Commissariat à l'Energie Atomique, Departement
de Protection, Fontenay-aux-Roses, France^a

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.

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.

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.

Pulsed ultrasound with short and widely-spaced pulses
(typically microsecond (µs) 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.

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 (theta_i) and
reflection (theta_r) 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 ( Z_o) 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.

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

p_x = p_oe^-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:

I_x = I_oe^-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
speed^a impedance^b coefficient^c coefficient
c Z_o=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 f^m,
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 I_aalpha_a; where alpha_a is the amplitude absorption
coefficient of the medium and I_a 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 I_a/rho C_m Equation 3.1

where d T/d t is the temperature rise per unit time, rho is the
ambient density of the medium, and C_m 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, C_m = 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 µm), which presumably occurs as a result of local absorption
mechanisms, will be insignificant in practice. This conclusion was
reached independently by Love & Kremkau (1980).

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 µm. 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 µm 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);

(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

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 cavity^a
------------------------------------------------------------------------------
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 field^a
--------------------------------------------------------------------
Physical situation D^x D^y
--------------------------------------------------------------------
Perfect absorber,
normal incidence^b
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
reflector^b
r = O or infinite 2 cos²theta 2 cos theta cos psi

Nonreflecting interface,
normal incidence^b
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/p_r)

where p is the acoustic pressure in free air. The reference
pressure p_r is usually taken as p_r=20 micropascals (µPa),
which is equivalent to an acoustic intensity of I_r=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/I_r)

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
(Lindström 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
(Lindström & 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 (Lindström 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.

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 ultrasound^a
--------------------------------------------------------------------------
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 industry^a
-----------------------------------------------------------------------------
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 ultrasound^a
---------------------------------------------------------------------------------
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 µs), 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
equipment^a
---------------------------------------------------------------------------------------------
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 ( I_a) (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 Ménière'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 µm.

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 µs, 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 µs-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-µs 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 µs) 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 µs, 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-µs 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 µs 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-µs 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 µs).

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 µs) 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).

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.

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;

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 µm. 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 (Möller 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

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'Electricité has produced a
standard for therapeutic ultrasound devices (Association française
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
française 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 Française 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
workplace^a
-----------------------------------------------------------------------
Sound pressure level within one-third octave band
(dB relative to 20 µPa)
--------------------------------------------------------
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.

Table 20. Limits of continuous exposure of the
general population to airborne acoustic energy^a
-----------------------------------------------
Mid-frequency of SPL within one-third octave
one-third octave (dB re: 20 µPa)
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;

(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.

REFERENCES

AAPM (1975) Statement on the use of diagnostic ultrasound
instrumentation on humans for training, demonstration and
research, General Medical Physics Committee of the AAPM. Med.
Phys., 2(1): 38.

AAPM (1979) Ultrasound instrument quality control
procedures. Maryland, American Association of Physicists in
Medicine, Cleaveland, Ohio, Chemical Rubber Publishing Co.,
p.45 (CRP Report Series - Report 3).

AAPM (1980) Pulse echo ultrasound imaging systems:
Performance tests and criteria, New York, American Institute
of Physics (American Association of Physicists in Medicine
Report No. 8).

ABDULLA U., CAMPBELL, S., DEWHURST, C.J., TALBERT, D., LUCAS,
M., & MULLARKEY, M. (1971) Effect of diagnostic ultrasound
on maternal and fetal chromosomes. Lancet, 2: 829-831.

ACGIH (1981) Threshold limit values for physical agents.
Cincinnati, Ohio, American Conference of Governmental
Industrial Hygienists, USA.

ACTON, W.I. (1968) A criterion for the prediction of
auditory and subjective effects due to airborne noise from
ultrasonic sources. Ann. occup. Hyg., II: 227-234.

ACTON, W.I. (1973) The effects of airborne ultrasound and
near ultrasound. In: International Congress on Noise as a
Public Health Problem. Dubrovnik, 14-18 May 1973, pp. 349-359.

ACTON, W.I. (1974) The effects of industrial airborne
ultrasound on humans. Ultrasonics, 12: 124-128.

ACTON, W.I. (1975) Exposure criteria for industrial
ultrasound. Ann. occup. Hyg., 18: 267-268.

ACTON, W.I. & CARSON, M.B. (1967) Auditory and subjective
effects of airborne noise from industrial ultrasonic sources.
Br. J. ind. Med., 24: 297-304.

ACTON, W.I. & HILL, C.E. (1977) Hazards of industrial
ultrasound. Protection, 14(19): 12-17.

AHRLIN, U. & OHRSTROM, B. (1978) Medical effects of
environmental noise on humans. J. Sound Vib., 59: 79-87.

AIUM (1974) 100 millimeter test object including standard
procedure for its use. Washington, DC, American Institute of
Ultrasound in Medicine.

AIUM (1978a) American Institute of Ultrasound in Medicine
bioeffects statement. Reflections, 4(4): 311 (also see "Who's
afraid of a hundred milliwatts per square centimeter (100
mW/cm², SPTA)?", brochure prepared by American Institute of
Ultrasound in Medicine Bioeffects Committee, Washington, DC).

AIUM (1978b) American Institute of Ultrasound in Medicine
standard on presentation and labeling of ultrasound images.
Reflections, 4: 70-75.

AIUM (1979) Standard specification of echoscope sensitivity
and noise level including recommended practice for such
measurements, Washington, DC, American Institute of Ultrasound
in Medicine.

AIUM (1980) Recommended nomenclature: Physics and
engineering, Washington, DC, American Institute of Ultrasound
in Medicine.

AIUM (1981) American Institute of Ultrasound in Medicine
standard for transducer characterization Washington, DC, American
Institute of Ultrasound in Medicine.

AIUM-NEMA (1981) AIUM-NEMA safety standard for diagnostic
ultrasound equipment (Draft V, January 27, 1981), Washington,
DC, American Institute of Ultrasound in Medicine.

AKAMATSU, N. (1981) Ultrasound irradiation effects on
pre-implantation embryos. Acta Obstet. Gynaecol. Jpn., 33(7):
969-978.

AKAMATSU, N. & SEKIBA, K. (1977) Symposium on recent studies
in the safety of diagnostic ultrasound. Ultrasound irradiation
effect on pre-implanted embryos. Jpn. J. Med. Ultrason., 4:
274-278.

AKAMATSU, N., NIWA, K., SEKIBA, K., & UTSUMI, K. (1977)
Ultrasound irradiation effect on embryos (6). Effect of
continuous ultrasound irradiation on pre-implanted rat embryo
(2). Nippon Choompa Igakkai Koen-Rombunshu, 32: 151-152.

AKOPYAN, V.B. & SARVAZYAN, A.P. (1979) Investigations of
mechanisms of action of ultrasound on biological media and
object. Sov. Phys. Acoust., 25(3): 262-263.

AL-HASHIMI, A.H.M. & CHAPMAN, I.V. (1981) Modification of
ultrasound-induced changes in mammalian cells by increased
viscosity of medium and increased ambient pressure. Int. J.
Radiat. Biol., 38: 11-19.

ALLEN, C.H., BRINGS, H., & RUDNICK, I. (1948) Some
biological effects of intense high frequency airborne sound.
J. Acoust. Soc. Am., 20(1): 62-65.

AMIN, A., FOSTER, K.R., TERNES, J., & TAKASHIMA, S. (1981)
Lack of effect of pulsed ultrasound on the mammalian EEG.
Aviat. Space Environ, Med., 52: 604-607.

ANDERSON, D.W. & BARRETT, J.T. (1979) Ultrasound: A new
immunosuppressant. Clin. Immunol. Immunopathol., 14: 18-29.

ANDERSON, D.W. & BARRETT, J.T. (1981) Depression of
phagocytosis by ultrasound. Ultrasound Med. Biol., 7: 267-273.

ANDERSON, G.H., HELLUMS, J.D., MOAKE, J.L., & ALFREY, C.P.,
Jr (1978) Platelet response to shear stress: Changes in
serotonin uptake, serotonin release, and ADP induced
aggregation. Thromb. Res., 13: 1039-1047.

ANGELUSCHEFF, Z.D. (1954) Ultrasonics and progressive
deafness. J. Acoust. Soc. Am., 26: 942 (abstract).

ANGELUSCHEFF, Z.D. (1955) Sonochemistry and the organ of
hearing. J. Acoust. Soc. Am., 27: 1009.

ANGELUSCHEFF, Z.D. (1967) Ultrasonics, resonance and
deafness. Rev. Laryngol. Otol. Rhinol., July-August.

APFEL, R.E. (1981) Acoustic cavitation. In: Edmonds, P.D.,
ed. Methods of experimental physics - ultrasonics, New York,
London, Toronto, Sydney, and San Francisco, Academic Press,
Vol 19, pp. 356-411.

ARSLAN, M., GREPALDI, G., GRANDESSO, R., MOLINARI, G.A.,
MUGGEO, M., & RICCI, V. (1973) Direct ultrasonic irradiation
of the hypophysis, Padua, Piccin Medical Books.

ASBEL, Z.Z. (1965) [The effect of ultrasound and high
frequency noise upon the blood sugar level.] Gig. Tr. Prof.
Zabol., 9: 29-33 (in Russian) (Occup. Health Safety Abstr.).

ASSOCIATION FRANCAISE DE NORMALISATION (1963) Appareils à
ultrasons, Paris (Norme française NF C 74-306).

ASSOCIATION FRANCAISE DE NORMALISATION (1982) Appareils à
ultrasons utilisés en diagnostic, Paris (Norme française NF C
74-335).

BALAMUTH, L. (1967) The application of ultrasonic energy in
the dental field. In: Brown, B. & Gordon, D., ed. Ultrasonic
techniques in biology and medicine, London, Iliffe, pp.
194-205.

BAMBER, J.C., HILL, C.R., & KING, J.A. (1981) Acoustic
properties of normal and cancerous human liver - II.
Dependence of tissue structure. Ultrasound Med. Biol., 7:
135-144.

BANG, J. (1972) The intensity of ultrasound in the uterus
during examination for diagnostic purposes. Acta pathol.
microbiol. Scand., Section A., 80: 341-344.

BANG, J. & NORTHEVED, A. (1970) Ultrasonic equipment for
application of ultrasound with high effect to animals used for
experiments. Acta pathol. microbiol. Scand., Section A., 78:
219-230.

BANG, J. & NORTHEVED, A. (1972) A new ultrasonic method for
transabdominal amniocentesis. Am. J. Obstet. Gynec., 114:
599-601.

BARNETT, S.B. (1979) Bioeffects of pulsed ultrasound.
Austral. Phys. Sci. Med., 2-7: 397-403.

BARNETT, S.B. & KOSSOFF, G. (1977) Negative effect of long
duration pulsed irradiation on the mitotic activity in
regenerating rat liver. In: White, D. & Brown, R.E., ed.
Ultrasound in Medicine, New York and London, Plenum Press, Vol
3B, pp. 2033-2044.

BARTH, G. & WACHSMANN, F. (1949) Biological effects of
ultrasonic therapy. In: Report of the Erlangen Ultrasound
Congress, Stuttgart, pp. 162-205.

BEKHOME, A.K. (1977) [Leukergia reaction in patients
suffering from chronic tonsillitis before and after ultrasound
therapy.] Vestn. Otorinolaringol., 4: 62-65 (in Russian with
English abstract).

BELEWA-STAIKOWA, R. & KRASCHKOWA, A.M. (1967) Effects of
biophysical factors on the redox processes and biological
oxidation. Effect of ultrasonics on the protein content and
transaminase activity of organs. Radiobiol. Radiother., 8:
655-662.

BENDER, L.F., JANES, J.M., & HERRICK, J.F. (1954) Histologic
studies following exposure of bone to ultrasound. Arch. Phys.
Med. Rehab., 35: 555-559.

BERNAT, R., HRYNIEWIECKI, L., & STRABURZYNSKI, G. (1966a)
[Influence of ultrasonics on the behaviour of proteins and
simpler nitrogen components in the blood and certain organs,
and on blood osmolarity.] Acta Physiol. Pol., 17(2): 193-203
(in Polish).

BERNAT, R., HRYNIEWIECKI, L., & STRABURZYNSKI, G. (1966b)
[Proteins and amino acids in the cataract induced by
ultrasonics.] Acta Physiol. Pol., 17(2): 225-235 (in Polish).

BERNSTEIN, R.L. (1969) Safety studies with ultrasonic
Doppler technique - a clinical follow-up of patients and
tissue culture study. Obstet. Gynecol., 34(5): 707-709.

BEYER, R.T. & LETCHER, R. (1969) Physical ultrasonics, New
York, Academic Press.

BINDAL V.N. & KUMAR A. (1979) Effect of the density of
liquids used on the sensitivity of float method for ultrasonic
power measurement. J. pure. app. Ultrason. 1: 69-71.

BINDAL V.N. & KUMAR, A. (1980) Measurement of ultrasonic
power with a fixed path radiation pressure float method.
Acustica, 46: 223-225.

BINDAL, V.N., SINGH, V.R., & SINGH, G. (1980) Acoustic power
measurement of medical ultrasonic probes using a strain gauge
technique. Ultrasonics, l8: 28-31.

BORRELLI, M.J., BAILEY, K.I., & DUNN, F. (1981) Early
ultrasonic effects on mammalian CNS structure (chemical
synapses). J. Acoust. Soc. Am., 69(5): 1514-1517.

BOUCHER, R.M. & KRUETER, J. (1968) The fundamentals of the
ultrasonic atomization of medicated solutions. Ann. Allerg.,
26: 591-600.

BOYD, E., ABDULLA, U., DONALD, I., FLEMING, J.E.E., HALL,
A.J., & FERGUSON-SMITH, M.A. (1971) Chromosomal breakage and
ultrasound. Br. med. J., 2: 501-502.

BRENDEL, K., MOLKENSTRUCK, W., & REIBOLD, R. (1978) Targets
for ultrasonic power measurements. In: 3rd European Congress
on Ultrasonics in Medicine, Bologna, Oct. 1-5, 1978, pp.
473-476.

BROWN, G.G. (1967) Airborne ultrasonics - their effects upon
humans. Can. Hosp., 44: 55-56.

BROWN, C.H., LEVERETT, L.B., LEWIS, C.W., ALFREY, C.P., &
HELLUMS, J.D. (1975) Morphological, biochemical and
functional changes in human platelets subjected to shear
stress. J. lab. clin. Med., 86: 462-471.

BROWN, N., GALLOWAY, W.D., MONAHAN, J.C., & FISHER, B.
(1979) Postnatal behavior and development. In utero exposure
of mice to ultrasound and microwave radiation. In: Proceedings
of the Fifth FDA Science Symposium on "Methods for Predicting
Toxicity", Arlington, VA, Oct. 10-12, 1979.

BROWN, N., GALLOWAY, W.D., & HENTON, W.W. (1981) Reflex
development following in utero exposure to ultrasound. In:
Proceedings of the American Institute of Ultrasound in
Medicine, San Francisco, CA, Aug. 17-21.

BUCKTON, K.E. & BAKER, N.V. (1972) An investigation into
possible chromosome damaging effects of ultrasound on human
blood cells. Br. J. Radiol., 45: 340-342.

BUNDY, M.L., LERNER, J., MESSIER, D.L., & ROONEY, J.A.
(1978) Effects of ultrasound on transport in avian
erythrocytes. Ultrasound Med. Biol., 4: 259-262.

BURR, J.G., WALD, N., PAN, S., & PRESTON, K. Jr (1978) The
synergistic effect of ultrasound and ionizing radiation on
human lymphocytes. In: Evans, H.J. & Lloyd, D.C., ed.
Mutagen-induced chromosome damage in man, New Haven,
Connecticut, Yale University Press, pp.120-128.

BYALKO, N. (1964) Certain biochemical abnormalities in
workers exposed to high frequency noise. Excerpta Med., 17:
570.

CACHON, J., CACHON, M., & BRUNETON, J.H. (1981) An
ultrastructural study of the effect of very high frequency
ultrasound on a microtubular system. Biol. Cell, 40: 69.

CANADA, DEPARTMENT OF NATIONAL HEALTH AND WELFARE (1980a)
Guidelines for the safe-use of ultrasound, Part I - Medical
and paramedical applications. Safety Code-23 (Health and
Welfare, Canada, Publication, 80-EHD-59).

CANADA, DEPARTMENT OF NATIONAL HEALTH AND WELFARE (1980b)
Guidelines for the safe use of ultrasound, Part II -
Industrial and commercial applications. Safety Code-24.
(Health and Welfare, Canada, Publication, 80-EHD-60).

CANADA, DEPARTMENT OF NATIONAL HEALTH AND WELFARE (1981)
Ultrasound therapy devices regulation. Canada Gaz., Part II,
115(8): 1121-1126.

CARSON, P.L. (1980) Diagnostic ultrasound emissions and
their measurement. In: Fullerton, G. & Zagzebski, J., ed. 1980
AAPM Summer School Proceedings, New York, American Institute
of Physics.

CARSON, P.L., FISCHELLA, P.R., & OUGHTON, T.V. (1978)
Ultrasonic power and intensities produced by diagnostic
ultrasound equipment. Ultrasound Med. Biol., 3(4): 341-350.

CARSON, T.E. & FISHMAN, S. (1976) Biological effects of
ultrasound: skin and cutaneous blood vessels. Proc. West.
Pharmacol. Soc., 19: 36-39.

CARSTENSEN, E.L. (1982) Biological effects of low-temporal-
average intensity pulsed ultrasound. Bioelectromagnetics, 3:
147-156.

CARSTENSEN, E.L., BECROFT, S.A., LAW, W.L., & BARBEE, D.B.
(1981) Finite amplitude effects on the thresholds for lesion
production in tissues by unfocused ultrasound. J. Acoust. Soc.
Am., 70(2): 302-309.

CATALDO, F.L., MILLER, M.W., & GREGORY, W.D. (1973) A
description of ultrasonically-induced chromosomal anomalies in
Vicia faba. Radiat. Bot., 13: 211-213.

CHAN, A.K., SIGELMAN, R.A., & GUY, A.W. (1974) Calculations
of therapeutic heat generated by ultrasound in fat-muscle-bone
layers. IEEE Trans. Biomed. Eng., 21: 280-284.

CHAPMAN, I.V. (1974) The effect of ultrasound on the
potassium content of rat thymocytes in vitro. Br. J. Radiol.,
47: 411-415.

CHAPMAN, I.V., MACNALLY, N.A., & TUCKER, S. (1980)
Ultrasound-induced changes in rates of influx and efflux of
potassium ions in rat thymocytes in vitro. Ultrasound Med.
Biol., 6: 47-58.

CHATER, B.V. & WILLIAMS, A.R. (1977) Platelet aggregation
induced in vitro by therapeutic ultrasound. Thromb. Haemos.,
38: 640-651.

CHAUSSY, C., BRENDEL, W., & SCHNIEDT, E. (1980) Extra-
corporeally induced destruction of kidney stones by shock
waves. Lancet, 13: 1265-1268.

CHILD, S.Z., CARSTENSEN; E.L., & SMACHLO, K. (1980) Effects
of ultrasound on Drosophila - I. Killing of eggs exposed to
travelling and standing wave fields. Ultrasound Med. Biol., 6:
127-130.

CHILD, S.Z., CARSTENSEN, E.L., & LAM, S.K. (1981a) Effects of
ultrasound on Drosophila - III. Exposure of larvae to low-
temporal-average-intensity pulsed irradiation. Ultrasound Med.
Biol., 7: 167-173.

CHILD, S.Z., CARSTENSEN, E.L., & DAVIS, H.T. (1981b) Tests
for "miniature flies" following exposure of Drosophila
melanogester larvae to diagnostic levels of ultrasound. Exp.
cell Biol., 48: 461-466.

CHILD, S.Z., HARE, J.D., CARSTENSEN, E.L., VIVES, B., DAVIS,
J., ALDER, A., & DAVIS, H.T. (1981c) Test for the effects of
diagnostic levels of ultrasound on the immune response of
mice. Clin. Immunol. Immunopathol., 18: 299-302.

CHORAZAK, T. & KONECKI, J. (1966) The effect of ultrasonics
on the content of protein bound SH and SS groups in the mouse
epidermis. Acta Histochem., 25: 127-132.

CIARAVINO, V., FLYNN, H.G., & MILLER, M.W. (1981) Pulsed
enhancement of acoustic cavitation: a postulated model.
Ultrasound Med. Biol., 7: 159-166.

CLARKE, P.R. & HILL, C.R. (1969) Biological action of
ultrasound in relation to the cell cycle. Expl. Cell Res., 58:
443-444.

CLARKE, P.R. & HILL, C.R. (1970) Physical and chemical
aspects of ultrasonic disruption of cells. J. Acoust. Soc.
Am., 50: 649-653.

CLARKE, P.R., HILL, C.R., & ADAMS, K. (1970) Synergism
between ultrasound and X-rays in tumour therapy. Br. J.
Radiol., 43: 97-99.

COAKLEY, W.T. (1978) Biophysical effects of ultrasound at
therapeutic intensities. Physiotherapy, 64(6): 166-169.

COAKLEY, W.T. & NYBORG, W.L. (1978) Cavitation; dynamics of
gas bubbles; applications. In: Fry, F.J., ed. Ultrasound: Its
application in medicine and biology, Amsterdam, Elsevier
Publishing Co., pp. 77-159.

COAKLEY, W.T., HAMPTON, D., & DUNN, F. (1971) Quantitative
relationships between ultrasonic cavitation and effects upon
amoebae at 1 MHz. J. Acoust. Soc. Am., 50: 1546-1553.

COLES, R.R.A. & KNIGHT, J.J. (1965) The problems of noise in
the Royal Navy and Royal Marines. J. Laryngol. Otol., 79:
131-147.

COMBES, R.D. (1975) Absence of mutation following ultrasonic
treatment of Baccillus subtilis cells and transforming
deoxyribonucleic acid. Br. J. Radiol., 48: 306-311.

CONNOLLY, W. & FOX, F.E. (1954) Acoustic cavitation
thresholds in water. J. Acoust. Soc. Am., 26: 843-848.

CRABTREE, R.B. & FORSHAW, E.E. (1977) Exposure to ultrasonic
cleaner noise in the Canadian Forces, Ottawa (Dept of National
Defence, DCIEM Technical Report No. 77 X 45).

CRUM, L.A. & HANSEN, G.M. (1982) Growth of air bubbles in
tissue by rectified diffusion. Phys. Med. Biol., 27: 413-417.

CURTO, K.A. (1975) Early postpartum mortality following
ultrasound radiation. In: Annual Conference, American
Institute of Ultrasound in Medicine, Winston-Salem, 4-9 Oct.,
pp. 535-536 (abstract).

DANIELS, S., PATON, W., & SMITH, E.B. (1979) Ultrasonic
imaging system for the study of decompression induced air
bubbles. Undersea biomed. Res., 6: 197-209.

DANNER, P.A., ACKERMAN, E., & FRINGS, H.W. (1954) Heating of
haired and hairless mice in high intensity sound fields from 6
to 22 kc. J. Acoust. Soc. Am., 26: 731.

DAVID, H., WEAVER, J.B., & PEARSON, J.F. (1975) Doppler
ultrasound and fetal activity. Br. med. J., 2: 62-64.

DAVIES, H., SCHWARTZ, R., PFISTER, R., & BARNES, F. (1974)
Transmitted ultrasound for relief of obstruction in ureters
and arteries: current status. J. clin. Ultrasound, 2: 217-220.

DAVIES, H., BEAN, W.J., & BARNES, F.S. (1977) Breaking up of
residual gallstones with an ultrasonic drill. Lancet, 2(8032):
278-279.

DAVIS, H. (1948) Biological and physiological effects of
ultrasonics. J. Acoust. Soc. Am., 20: 605-607.

DAVIS, H., ed. (1958) Auditory and nonauditory effects of
high intensity noise, Pensacola, Florida, Central Institute
for the Deaf and Naval School of Aviation.

DeREGGI, A.S., ROTH, S.C., KENNEY, J.M., EDELMAN, S., &
HARRIS, G. (1978) Polymeric ultrasonic probe. J. Acoust.
Soc. Am., 64(1): 55 (abstract).

DeREGGI, A.S., ROTH, S.C., KENNEY, J.M., EDELMAN, S., &
HARRIS, G. (1981) Piezoelectric polymer probe for ultrasonic
applications. J. Acoust. Soc. Am., 69(3): 853-859.

DESCH, E.H., SPROULE, D.A., & DAWSON, W.J. (1946) The
detection of cracks in steel by means of supersonic waves.
J.Steel Inst., 153: 319.

DEWITZ, T.S., MARTIN, R.R., SOLIS, R.T., HELLUMS, J.D., &
McINTIRE, L.V. (1978) Microaggregate formation in whole
blood exposed to shear stress. Microvasc. Res., 16: 263-271.

DEWITZ, T.S., McINTIRE, L.V., MARTIN, R.R., & SYBERS, H.D.
(1979) Enzyme release and morphological changes in leukocytes
induced by mechanical trauma. Blood Cells, 5: 499.

DICKSON, J.A. & ELLIS, H.A. (1974) Stimulation of tumor cell
dissemination by raised temperature (42 °C) in rats with
transportable Yoshida tumors. Nature (Lond.), 248: 354-358.

DOBROSERDOV, V.K. (1967) [The effects of low frequency
ultrasonic and high frequency sound waves on workers.] Gig. i
Sanit., 32: 17-21 (in Russian).

DUMONTIER, A., BURDICK, A., EWIGMAN, B., & FAHIM, M.S.
(1977) Effects of sonication on mature rat testes. Fertil.
Steril., 28(2): 195-204.

DUNN, F. (1965) Ultrasonic absorption by biological
materials. In: Kelly, E., ed. Ultrasonic energy. Illinois,
University of Illinois Press, pp. 51-65.

DUNN, F. & COAKLEY, W.T. (1972) Interaction of ultrasound
and microorganisms in suspension. In: Reid, J.M. & Sikov,
M.R., ed. Interaction of ultrasound with biological tissues,
Washington, DC, US Government Printing Office, pp. 65-68 (US
Dept HEW Publ. (FDA) 73-8008).

DUNN, F. & FRY, F.J. (1971) Ultrasonic threshold dosages for
the mammalian central nervous system. IEEE Trans. Biomed.
Eng., BME-18: 253-256.

DUNN, F. & POND, J.B. (1978) Selected non-thermal mechanisms
of interaction of ultrasound and biological media. In: Fry,
F.J., ed. Ultrasound: Its application in medicine and biology,
Part II, Amsterdam, Oxford, and New York, Elsevier Sci. Publ.
Co., pp. 539-559.

DYER, H.J. (1965) Changes in behaviour of mosses treated
with ultrasound. J. Acoust. Soc. Am., 37: 1195A.

DYER, H.J. (1972) Structural effects of ultrasound on the
cell. In: Reid, J.M. & Sikov, M.R., ed. Interaction of
ultrasound with biological tissues, Washington, DC, pp. 73-75
(US Dept HEW Publ. (FDA) 73-8008).

DYSON, M. & POND, J. (1973) Effects of ultrasound on
circulation. Physiotherapy, 59(9): 284-287.

DYSON, M., POND, J.B., JOSEPH, J., & WARWICK, R. (1968) The
stimulation of tissue regeneration by means of ultrasound.
Clin. Sci., 35: 273-285.

DYSON, M., POND, J.B., & WARWICK, R. (1970) Stimulation of
tissue regeneration by pulsed-wave ultrasound. IEEE Trans.
Son. Ultrason., SU-17: 133-140.

DYSON, M., WOODWARD, B., & POND, J.B. (1971) Flow of red
blood cells stopped by ultrasound. Nature (Lond.), 232:
572-573.

DYSON, M., POND, J.B., WOODWARD, B., & BROADBENT, J. (1974)
The production of blood cell stasis and endothelial damage in
the blood vessels of chick embryos treated with ultrasound in
a stationary wave field. Ultrasound Med. Biol., 1: 133-148.

DYSON, M., FRANKS, C., & SUCKLING, J. (1976) Stimulation of
healing of varicose ulcers by ultrasound. Ultrasonics, 14:
232-236.

EDMONDS, P.D. (1972) Effects on macromolecules. In: Reid,
J.W. & Sikov, M.R., ed. Interaction of ultrasound and
biological tissues, Washington, DC, Government Printing
Office, pp. 5-11 (US Dept HEW Publ. (FDA) 73-8008).

EDMONDS, P.D. (1980) Further skeptical comment on reported
adverse effects of alleged low intensity ultrasound. In:
Proceedings of the 25th American Institute of Ultrasound in
Medicine Conference, New Orleans, Washington, DC, American
Institute of Ultrasound, p. 50.

EDMONDS, P.D., STOLZENBERG, S.J., TORBIT, C.A., MADAN, S.M., &
PRATT, D.E. (1979) Post-partum survival of mice exposed in
utero to ultrasound. J. Acoust. Soc. Am., 66(2): 590-593.

ELDER, S.A. (1959) Cavitation microstreaming. J. Acoust.
Soc. Am., 31: 54-64.

ELDRIDGE, D.H., Jr (1950) Some responses of the ear to high
frequency sound. Am. Soc. Exp. Biol. fed. Proc., 9: 37.

ELMER, W.A. & FLEISCHER, A.C. (1974) Enhancement of DNA
synthesis in neonatal mouse tibial epiphyses after exposure to
therapeutic ultrasound. J. clin. Ultrasound, 2: 191-195.

EL'PINER, I.E. (1964) Ultrasound - physical, chemical, and
biological effects. (Translated from Russian, Consultants
Bureau, New York).

EMERY, J.M. (1974) Phacoemulsification. In: Emery, J.M. &
Paton, D., ed. Proceedings of the Third Biannual Cataract
Surgery Congress, St. Louis, Mosby Co., pp. 207-208.

EMERY, J.M. & PATON, D. (1974) Phacoemulsification: A survey
of 2875 cases. In: Emery, J.M. & Paton, D., ed. Proceedings of
the Third Biannual Cataract Surgery Congress, St. Louis, Mosby
Co., pp. 222-224.

EMERY, J.M., LANDIS, D.J., & BENOLKEN, R.M. (1974) The
phacoemulsifier: an evaluation of performance. In: Emery, J.M.
& Paton, D., ed. Proceedings of the Third Biannual Cataract
Surgery Congress, St. Louis, Mosby Co., pp. 208-222.

ESCHE, R. (1952) [Investigation of cavitation by sound in
liquids.] Akust. Beihefte, 4: 208-218 (in German).

ESMAT, N. (1975) Investigations of the effects of different
doses of ultrasonic waves on the human nerve conduction
velocity. J. Egypt. Med. Assoc., 53: 395-402.

ETIENNE, J., FILIPCZYNSKI, L., FIREK, A., GRONIOWSKI, J.,
LYPACEWICZ, G., & SALKOWSKI, J. (1976) Intensity deter-
mination of ultrasonic focused beams used in ultrasonography
in the case of gravid uterus. Ultrasound Med. Biol., 2:
119-122.

EVANS, A. & WALDER, D.N. (1970) Detection of circulating
bubbles in the intact animal. Ultrasonics, 8: 216-217.

FAHIM, M.S., FAHIM, Z., DER, R., HALL, D.G., & HARMAN, J.
(1975) Heat in male contraception (hot water 60 °C, infrared,
microwave and ultrasound). C ontraception, 11(5): 549-562.

FAHIM, M.S., FAHIM, Z., HARMAN, J., THOMPSON, L., MONTIE, J.,
& HALL, D.G. (1977) Ultrasound as a new method of male
contraception. Fertil. Steril., 28(8): 823-831.

FALLON, J.T., STEPHENS, W.E., & EGGLETON, R.C. (1973) An
ultrastructural study of the effect of ultrasound on arterial
tissue. J. Pathol., 111: 275-284.

FALUS, M., KORANYI, G., SOBEL, M., PESTI, E., & TRINK, V.B.
(1972) Follow-up studies on infants examined by ultrasound
during the fetal age. Orvosi Hetilap, 13: 2119-2121.

FARMER, W.C. (1968) Effect of intensity of ultrasound on
conduction of motor axons. Phys. Ther., 48(11): 1233-1237.

FARMERY, M.J. & WHITTINGHAM, T.A. (1978) A portable
radiation force balance for use with diagnostic ultrasonic
equipment. Ultrasound Med. Biol., 3: 373-379.

FINKLER, H. & HAUSLER, E. (1976) Focusing of ultrasonic
shockwaves for the touchless destruction of kidney stones. In:
Ultrasonics Symposium Proceedings, Annapolis, Maryland, pp.
97-99.

FIRESTONE, F.A. (1945) The supersonic reflectoscope for
internal inspection. Met. Prog., 48: 505-512.

FISHMAN, S.S. (1968) Biological effects of ultrasound in vivo
and in vitro haemolysis. Proc. West. Pharmacol. Soc., 11:
149-150.

FLYNN, H.G. (1964) Physics of acoustic cavitation in
liquids. In: Mason, W.P., ed. Physical acoustics, New York,
Academic Press. Vol 1B, pp. 57-172.

FORREST, J.O. (1967) Ultrasonic scaling, a 5-year
assessment. Br. dental J., 122: 9-14.

FOSTER, K.R. & WIEDERHOLD, M.L. (1978) Auditory responses in
cats produced by pulsed ultrasound. J. Acoust. Soc. Am., 63:
1199-1205.

FRANKLIN, T.D., EGENES, K.M., FALLON, J.T., SANGHVI, N.T., &
FRY, F.J. (1977) Therapeutic applications of ultrasound in
myocardial infraction: A chronic six-week study in dogs.
Presented at: American Institute of Ultrasound in Medicine
Meeting, Dallas, Texas, Washington, DC, AIUM.

FREDERIKSEN, E. (1977) Condenser microphones used as sound
sources. Brüel Kjaer tech. Rev., 3: 3-32.

FRITZ-NIGGLI, H. & BONI, A. (1950) Biological experiments on
Drosophila melanogaster with supersonic vibrations. Science,
112: 120-122.

FROST, H.M. (1977) Heating under ultrasonic dental scaling
conditions. In: Symposium on Biological Effects and
Characterizations of Ultrasound Sources, Washington, DC, US
DHEW, pp. 64-76 (US Dept HEW Publ. (FDA) 78-8048).

FRY, F.J. & BARGER, J.E. (1978) Acoustic properties of the
human skull. J. Acoust. Soc. Am., 63: 1576-1590.

FRY, W.J. & DUNN, F. (1956) Ultrasonic irradiation of the
central nervous system at high sound levels. J. Acoust. Soc.
Am., 28: 129-131.

FRY, F.J., ADES, H.W., & FRY, W.J. (1958) Production of
reversible changes in the central nervous system by
ultrasound. Science, 127: 83-84.

FRY, F.J., KOSSOFF, G., EGGLETON, R.C., & DUNN, F. (1970)
Threshold ultrasonic dosages for structural changes in the
mammalian brain. J. Acoust. Soc. Am., 48: 1416-1417.

FRY, F.J., JOHNSON, L.K., & ERDMANN, W.A. (1978) Interaction
of ultrasound with solid tumours in vivo and tumour cell
suspensions in vitro. In: White, D. & Lyons, E.A. ed.
Ultrasound in medicine, New York, Plenum Press, Vol. 4., pp.
587-588.

FUNG, H.K., CHEUNG, K., LYONS, E.A., & KAY, N.E. (1978) The
effects of low-dose ultrasound on human peripheral lymphocyte
function in vitro. In: White, D. & Lyons, E.A., ed. Ultrasound
in medicine, New York, Plenum Press, Vol. 4, pp. 583-586.

GALPERIN-LEMAITRE, H., GUSTOT, P., & LEVI, S. (1973)
Ultrasound and marrow-cell chromosomes. Lancet, 2: 505-506.

GALPERIN-LEMAITRE, H., KIRSCH-VOLDERS, M., & LEVI, S. (1975)
Ultrasound and mammalian DNA. Lancet, 2: 662.

GAVRILOV, L.R., NARBUT, N.P., & FRIDMAN, F.E. (1974) [Use of
focused ultrasound to accelerate the "mating" of a cataract.]
Akustic. Z. (USSR), 20: 274-377 (in Russian).

GAVRILOV, L.R., TSIRULNIKOV, E.M., & SHCHEKANOV, E.E. (1975)
[Stimulation of auditory receptors by focused ultrasound.]
Sov. Phys. Acoust., 21(5): 437-489 (in Russian).

GAVRILOV, L.R., GERSUNI, G.V., ILYINSKI, O.B., SIROTYUK, M.G.,
TSIRULNIKOV, E., & SHCHEKANOV, E.E. (1976) The effect of
focused ultrasound on the skin and deep nerve structures of
man and animal. Brain Res., 43: 279-292.

GAVRILOV, L.R., GERSUNI, G.V., ILYINSKI, O.B., TSIRULNIKOV,
E.M., & SHCHEKANOV, E.E. (1977) A study of reception with
the use of focused ultrasound - effects on the skin and deep
receptor structures in man. Brain Res., 135(2): 265-277.

GERASIMOVA, E.J. (1976) [A study of the effect of ultrasound
on the sympathicoadrenal system of workers.] Gig. i Sanit., 8:
23-29 (in Russian).

GERNER, E.W., BOONE, R., CONNER, W.G., HICKS, J.A., & BOONE,
M.M. (1976) A transient thermotolerant survival response
produced by single thermal doses in Hela cells. Cancer Res.,
36: 1035-1040.

GERSHOY, A. & NYBORG, W.L. (1973) Perturbation of plant-cell
contents by ultrasonic microirradiation. J. Acoust. Soc. Am.,
54(5): 1356-1367.

GERSTEN, J.W. (1955) Effect of ultrasound on tendon
extensibility. Am. J. phys. Med., 34: 362-369.

GIRARD, L.J. (1974) Ultrasonic aspiration - irrigation of
cataract and the vitreous. In: Emery, J.M. & Paton, D.J., ed.
Proceedings of the Third Biannual Cataract Surgical Congress.
Current concepts in cataract surgery, St. Louis, Mosby Co.,
pp. 194-197.

GLICK, D., ADAMOVICS, A., EDMONDS, P.D., & TAENZER, J.C.
(1979) Search for biochemical effects in cells and tissues of
ultrasonic irradiation of mice and of the in vitro irradiation
of mouse peritoneal and human amniotic cells. Ultrasound Med.
Biol., 5: 23-33.

GLICK, D., NOLAN, H.W., & EDMONDS, P.D. (1981) Blood
chemical and haematological effects of ultrasonic irradiation
of mice. Ultrasound Med. Biol., 7: 87-90.

GLOERSON, W.R., HARRIS, G.R., STEWART, H.F., & LEWIN, P.A.
(1982) A comparison of two calibration methods for ultrasonic
hydrophones. Ultrasound Med. Biol., 8: 545-548.

GLOVER, C.J., McINTIRE, L.V., LEVERETT, L.B., HELLUMS, J.D.,
BROWN, C.H., & NATELSON, E.A. (1974) Effect of shear stress
on clot structure formation. Trans. Am. Soc. Artif. Int. Org.,
20: 463-468.

GOLDBLAT, V.I. (1969) [Processes of bone tissue regeneration
under the effect of ultrasound.] Ortoped. Travmoto.
Proteziro., 30: 57-61 (in Russian).

GOLDSTEIN, A. (1982) Quality assurance in diagnostic
ultrasound. In: Repacholi, M.H. & Benwell, D.A., ed.
Essentials of medical ultrasound, New Jersey, Humana Press,
pp. 215-280.

GOLIAMINA, L.P. (1974) Ultrasonic surgery. In: Proceedings
of the 8th International Congress on Acoustics, Guildford UK,
IPC Science and Technology Press, pp. 63-69.

GORALCUK, M.V. & KOSIK, T.F. (1976) [The effects of
ultrasound on histological and histochemical changes in the
healing process of suppurative ulcers of the cornea.]
Ofthalmol. Z., 31(7): 533-535 (in Russian).

GORSLIKOV, S.I., GOREUNOV, O.N., & ANTROPOV, S.A. (1965)
Biological effects of ultrasound. Ultrasonics, 4: 211.

GOSS, S.A., COBB, J.W., & FRIZZELL, L.A. (1977) Effect of
beam width and thermocouple size on the measurement of
ultrasonic absorption using thermoelectric technique. In: 1977
Ultrasonic Symposium Proceedings, New York, IEEE, pp. 206-211.

GREGORY, W.D., MILLER, M.W., CARSTENSEN, E.L., CATALDO, F.L.,
& REDDY, M.M. (1974) Nonthermal effects of 2 MHz ultrasound
on the growth and cytology of Vicia faba roots. Br. J.
Radiol., 47: 122-129.

GRIGOR'EVA, V.M. (1966a) Effect of ultrasonic vibrations on
personnel working with ultrasonic equipment. Sov. Phys.
Acoust., 11: 426-427.

GRIGOR'EVA, V.M. (1966b) [Ultrasound and the question of
occupational hazards.] Mascinstreocija, 8: 32 (in Russian)
(Abstract in Ultrasonics, 4: 214).

HAHN, G.M., BRAUN, J., & HAR-KEDAR, I. (1975) Thermo-
chemotherapy synergism between hyperthermia (42-43 degrees)
and adriamycin (or bleomycin) in mammalian cells inactivation.
Proc. Natl Acad. Sci. USA, 72:: 937-940.

HARA, K. (1980) Effect of ultrasonic irradiation on
chromosomes, cell division and developing embryos. Acta Obst.
Gynaecol. Jpn., 32(1): 61-68.

HARA, K., MINOURA, S., OKAI, T., & SAKAMOTO, S. (1977)
Symposium on recent studies in the safety of diagnostic
ultrasound. Safety of ultrasonics on organism. Jpn. J. med.
Ultrasonics, 4: 256-258.

HARRIS, G.R. (1981) Detection and analysis of transient
ultrasonic fields: A study using polyvinylidene fluoride
piezoelectric polymer hydrophones. PhD Thesis, Catholic
University of America, Washington, DC.

HARRIS, G.R., HERMAN, B.A., HARAN, M.E., & SMITH, S.W.
(1977) Calibration and use of miniature ultrasonic
hydrophones. In: Symposium on Biological Effects and
Characterization of Ultrasound Sources, Wasington, DC, US
DHEW, pp. 169-174 (US Dept HEW Publ. (FDA) 78-8048).

HARVEY, W., DYSON, M., POND, J.B., & GRAHAME, R. (1975) The
in vitro stimulation of protein synthesis in human fibroblasts
by therapeutic levels of ultrasound. In: Kazner, E. et al.,
ed. Proceedings of the 2nd European Congress on Ultrasonics in
Medicine, Munich 12-16 May 1975, Amsterdam, Excerpta Medica,
pp. 10-21. (Excerpta Medica International Congress Series No.
363).

HAUPT, M., MARTIN, A.O., SIMPSON, J.L., IQBAL, M.A., ELIAS,
S., & SABBAGHA, R.E. (1981) Ultrasonic induction of sister
chromatid exchanges in human lymphocytes. Human Genet., 59:
221-226.

HELLMAN, L.M., DUFFUS, G.M., DONALD, L., & SUNDEN, B. (1970)
Safety of diagnostic ultrasound in obstetrics. Lancet, 1:
1133-1135.

HEIMBURGER, R.F., FRY, F.J., FRANKLIN, T.D., & EGGLESTON,
R.C. (1975) Ultrasound potentiation of chemotherapy for
brain malignancy. In: White, D., ed. Ultrasound in medicine,
New York, Plenum, Press, Vol l., p. 273.

HERMAN, B.A. & POWELL, D. (1981) Airborne ultrasound:
Measurement and possible adverse effects, Washington, DC, (US
Dept Health and Human Services, HHS Publ. (FDA) 81-8163).

HERTZ, R.H., TIMOR TRITSCH, I., DIERKER, L.J., CHIK, L., &
ROSEN, M.G. (1979) Continuous ultrasound and fetal movement.
Am. J. Obstet. Gynecol., 135(1): 152-154.

HILL, C.R. (1971) Acoustic intensity measurement on
ultrasonic diagnostic devices. In: Bock, J. & Ossoinig, K.,
ed. Ultrasongraphia medica, Vienna, Vienna Academy of
Medicine, pp. 21-27.

HILL, C.R. (1972a) Ultrasonic exposure thresholds for
changes in cells and tissues. J. Acoust. Soc. Am., 52: 667-672.

HILL, C.R. (1972b) Interaction of ultrasound with cells. In:
Reid, J.M. & Sikov, M.R., ed. Interaction of ultrasound with
biological tissues, Washington, DC, US DHEW, pp. 57-79 (US
Dept HEW Publ. (FDA) 73-8008).

HILL, C.R. & JOSHI, G.P. (1970) The significance of
cavitation in interpreting the biological effects of
ultrasound. In: Proceedings of a Conference on Ultrasonics in
Biology and Medicine, Warsaw, UBIOMED-70, pp. 125-131.

HILL, C.R. & TER HAAR, G. (1981) Ultrasound. In: Suess,
M.J., ed. Nonionizing radiation protection, Copenhagen, World
Health Organization Regional Office for Europe (WHO Regional
Publications, European Series No. 10).

HILL, C.R., CLARKE, P.R., CROWE, M.R., & HAMMICK, J.W.
(1969) Biophysical effects of cavitation in an 1 MHz
ultrasonic beam. In: Ultrasonics for Industry Conference
Papers, 1969, pp. 26-30.

HILL, C.R., JOSHI, G.P., & REVELL, S.H. (1972) A search for
chromosome damage following exposure of Chinese hamster cells
to high intensity, pulsed ultrasound. Br. J. Radiol., 45:
333-334.

HODGSON, W.J.B., BAKARE, S., HARRINGTON, E., FINKELSTEIN, J.,
PODDAR, P.K., LOSCALZO, L.L., WEITZ, J., & McELHINNEY, A.J.
(1979) General surgical evaluation of a powered device
operating at ultrasonic frequencies. Mt Sinai J. Med. (NY),
46(2): 99-103.

HOUNSFIELD, G.N. (1973) Computerized traverse axial scanning
(tomography), Part I. Description of system. Br. J. Radiol.,
46: 1016-1022.

HRAZDIRA, I. & ADLER, J. (1980) Electrokinetic properties of
isolated cells exposed to low levels of ultrasound. In:
Ultrasound Interactions in Biology in Medicine, International
Symposium, Nov. 10-14, Casel Reinhardsbrunn-GDR, p. C-11.

HRAZDIRA, I. & HAVELKOVA, M. (1966) Ultrasound and the
ultramicroscopic structure of Rhizopus nigricans.
Naturwissenschaften, 53: 206.

HRAZDIRA, I. & KONECNY, M. (1966) Functional and morpho-
logical changes in the thyroid gland after ultrasonic
irradiation. Am. J. Phys. Med., 45(5): 238-243.

HU, J.H. & ULRICH, W.D. (1976) Effects of low-intensity
ultrasound on the central nervous system of primates. Aviat.
Space environ. Med., 47(6): 640-643.

HU, J.H., TAYLOR, J.D., PRESS, H.C., & WHITE, J.E. (1978)
Ultrasonic effects on mammalian interstitial muscle membrane.
Aviat. Space environ. Med., 49(4): 607-609.

HUETER, T.F. & BOLT, R.H. (1955) Sonics. In: Radiation
pressure, New York, Wiley, pp. 43-53.

HUG, O. & PAPE, R. (1954) Establishing the presence of
ultrasound cavitation in tissues. Stralentherapie, 94: 79-99
(translated from German).

HUSTLER, J.E., ZAROD, A.P., & WILLIAMS, A.R. (1978)
Ultrasonic modification of experimental bruising in the
guinea-pig pinna. Ultrasonics, 16(5): 223-228

IDE, M. & OHIRA, E. (1975) Measurement of ultrasonic noise
radiated from ultrasonic cleaners. In: Proceedings of the
Acoustical Society of Japan, pp. 135-136

IERNETTI, G. (1971) Cavitation threshold dependence on
volume. Acustica, 24: 191-196.

IEC (1980a) Draft: IEC Standard Publication 601-2-XX.
Ultrasonic Medical Diagnostic Equipment, Part 2. Particular
requirements for safety (IEC/TC 62D (Sec) 31, Dec. 1980).

IEC (1980b) Draft: Ultrasonic therapy equipment, particular
requirements for safety (IEC/TC 62/SC 62D (Sec.) 25, Dec.
1980).

IEC (l981) Draft: Characteristics and calibration of
hydrophones for operation in the frequency range 0.5 to l5 MHz
(IEC/TC 29/SC 29D (Central Office) 19).

IEC (1982) Draft: Methods of measuring the performance of
ultrasonic pulse-echo diagnostic equipment (IEC/TC 29/SC 29D
(central Office) 16, February 1982).

IKEUCHI, T., SASAKI, M., OSHIMURA, M., AZUMI, J., TSUJI, K., &
SHIMIZU, T. (1973) Ultrasound and embryonic chromosomes.
Br.med. J., 1: 112.

ILO (1977) Protection of workers against noise and vibration
in the working environment, Geneva, International Labour
Organization, pp. 66 (ILO Codes of Practice).

IRPA (1977) Overviews on non-ionizing radiation. Washington,
DC, International Radiation Protection Association, US Dept of
Health, Education and Welfare, pp. 42-59.

IRPA (1981) Draft: Guidelines on limits of human exposure to
airborne acoustic energy having one-third octave bands with
mid frequencies from 8 to 50 kHz. International Radiation
Protection Association, International Non-Ionizing Radiation
Committee (IRPA/INIRC), Nov. 1981.

JACKE, S.E. (1979) Ultrasonics in industry today. In:
Proceedings Ultrasonics International 1979, Graz, Austria,
Guildford, UK, IPC Science and Technology Press.

JACOBSON, E.J., DOWNS, M.P., & FLETCHER; J.L. (1969) Clinical
findings in high frequency thresholds during known drug usage.
J. aud. Res., 9: 379.

JAMES, J.A. (1963) New developments in ultrasonic therapy of
Ménière's disease. Ann. R. Coll. Surg. Engl., 33: 226-244.

JANKOWIAK, J. & MAJEWSKI, C. (1966) Electron-microscope
studies of acid phosphates in neutrophilic granulocytes in the
blood of rabbits subjected to ultrasound. Am. J. phys. Med.,
45(1): 1-7.

JAPANESE MINISTRY OF LABOUR (1971) Airborne ultrasound
standard, order by Chief of the Labour Standard Bureau based
on the Circular 326 of the Japanese Ministry of Labour.
Guidelines on the use of ultrasonic welder, Tokyo, Japan.

JIS (1979) Japanese Industrial Standards. Ultrasonic Doppler
fetal diagnostic equipment (draft, March 1979). Tokyo, Japan,
Electronic Industries Association of Japan.

JIS (1980) Japanese Industrial Standards, Draft: M-mode
ultrasonic diagnostic equipment. Tokyo, Japan.

JIS (1981) Japanese Industrial Standards. Draft: Methods of
measuring the performance of ultrasonic pulse-echo diagnostic
equipment. Tokyo, Japan.

JOHNSON, A. & LINDVALL, A. (1969) Effects of low-intensity
ultrasound in viscous properties of elodea cells.
Naturwissenschaft, 56: 40.

JOHNSON, W.N. & WILSON, J.R. (1957) The application of the
ultrasonic dental unit to scaling procedures. J. Periodontol.,
23: 264-271.

JOSHI, G.P., HILL, C.R., & FORRESTER, J.A. (1973) Mode of
action of ultrasound on the surface change of mammalian cells
in vitro. Ultrasound Med. Biol., 1: 45-48.

JSA (1976) Japanese Standards Association, Draft: A-mode
ultrasonic diagnostic equipment. Tokyo, Japan.

JSA (1978) Japanese Standards Association, Draft: Japanese
Industrial Standard, Manual scanning B-mode ultrasonic
diagnostic equipment, March, Tokyo, Japan.

KARDUCK, A. & WEHMER, W. (1974) Morphologic studies of the
influence of ultrasound upon the growing rabbit's larynx.
Arch. Oto-Rhinol.-Laryngol., 206: 137-154.

KATO, M. (1969) Ultrasonic effects affecting the mechanism
of reproduction of micronsized microorganism. J. Phys. Soc.
Jpn, 31: 31-32.

KAUFMANN, J.S. & KREMKAU, F.W. (1978) Influence of
ultrasound on mouse leukaemia cell CNA synthesis, membrane
integrity, and uptake of anticancer drugs in vitro. In: White,
D. & Lyons, E.A., ed. Ultrasound in medicine, New York, Plenum
Press, Vol. 4, pp. 589-590.

KAUFMAN, G.E. & MILLER, M.W. (1978) Growth retardation in
Chinese hamster V-79 cells exposed to 1 MHz ultrasound.
Ultrasound Med. Biol., 4: 139-144.

KAUFMAN, G.E., MILLER, M.W., GRIFFITHS, T.D., CIARAVINO, V., &
CARSTENSEN, E.L. (1977) Lysis and viability of cultured
mammalian cells exposed to 1 MHz ultrasound. Ultrasound Med.
Biol., 3: 21-25.

KELMAN, C.D. (1967) Phaco-emulsification and aspiration: A
new technique of cataract removal. Am. J. Ophthalmol., 64:
23-35.

KHOE, W.H. (1977) Ultrasound acupuncture: effective
treatment modality for various diseases. Am. J. Acupunct.,
5(1): 31-34.

KINSLER, L.E. & FREY, P. (1962) Fundamentals of acoustics,
New York, J. Wiley Press.

KISHI, M., MISHIMA, T., ITAKURA, T., TSUDA, K., & OKA, M.
(1975) Experimental studies of effects of intense ultrasound
on implantable murine glioma. In: Kazner, E., de Vliger, M.,
Muller, H.R. & McCready, V.R., ed. Ultrasonics in medicine,
Amsterdam, Excerpta Medica, pp. 28-33.

KLEINSCHMIDT, P. & MAGORI, V. (1981) Ultrasonic remote
sensors for noncontact object detection. Siemans Forsch-u.
Entwickl.-Ber., 10(2): 110-118.

KNIGHT, J.J. (1968) Effects of airborne ultrasound on man.
Ultrasonics, 6: 39-42.

KNIGHT, J.J. & COLES, R.R.A. (1966) A six-year prospective
study of the effect of jet aircraft noise on hearing.
J. R. Nav. Med. Serv., 52: 92.

KOH, S. (1981) The safety of diagnostic continuous wave
ultrasonic irradiation - a clinical study. Serum hemoglobin
level and scanning electron microscopic finding of maternal
and cord blood in vitro. Acta Obstet. Gynaec. Jpn., 33:
469-478.

KOIFMAN, M.M., VACILIEVA, T.N., MASLOV, K.I., MAEV, R.G., &
LEVIN, V.M. (1980) Antibody secretion changes induced by
ultrasound in lymphoid cells. In: Ultrasound Interaction in
Biology and Medicine. International Symposium, Nov. 10-14,
1980. Castle Reinhardsbrunn-GDR, p. C-16.

KOLAR, J., BABICKJ, A., KASLOVA, J., & KASI, J. (1965) [The
effect of ultrasound on the mineral metabolism of bones.]
Travmatol. protezinov., 26(8): 43-51 (in Russian).

KOSSOFF, G. (1978) On the measurement and specification of
acoustic output generated by pulse ultrasonic diagnostic
equipment. J. clin. Ultrasound, 6(5): 303-309.

KOSSOFF, G. & KHAN, A.E. (1966) Treatment of vertigo using
the ultrasonic generator. Arch. Otolaryngol., 84: 181-188.

KREMKAU, F.W. (1979) Cancer therapy with ultrasound: a
historical review. J. clin. Ultrasound, 7: 287-300.

KREMKAU, F.W. & CARSTENSEN, E.L. (1972) Macromolecular
interaction in sound absorption. In: Reid, J.M. & Sikov, M.R.,
ed. Interaction of ultrasound and biological tissues,
Washington, DC, US DHEW, pp. 37-42 (US Dept HEW Publ. (FDA)
73-8008).

KREMKAU, F.W. & WITCOFSKI, R.L. (1974) Mitotic reduction in
rat liver exposed to ultrasound. J. clin. Ultrasound, 2(2):
123-126.

KUNZE-MUHL, E. (1981) Observation of the effect of X-rays
alone and in combination with ultrasound on human chromosomes.
Human Genet., 57: 257-260.

KURACHI, K., CHIBA, Y., SUEHARA, N., & SAKUMOTO, T. (1981)
Studies on the effect of pulsed ultrasound on chromosome and
erythrocyte, and optimal utility of ultrasound diagnosis in
early pregnancy. Jpn. J. med. Ultrason. 8: 271-273.

LATT, S.A. & SCHRECK, R.R. (1980) Sister chromatid exchange
analysis. Am. J. Hum. Genet., 32(3): 297-313.

LEHMANN, J.F. (1965a) Ultrasonic diathermy. In: Krusen,
F.H., Kottke, F.J., & Ellerwood, P., ed. Handbook of physical
medicine and rehabilitation, Philadelphia and London, W.B.
Saunders Co., pp. 271-299.

LEHMANN, J.F. (1965b) Ultrasound and therapy. In: Licht, E.
& Kamenetz, H.L., ed. Therapeutic heat and cold. 2nd ed.,
Baltimore, Maryland, Waverley Press Inc., pp. 321-386.

LEHMANN, J.F. & GUY, A.W. (1972) Ultrasound therapy. In:
Reid, J.M. & Sikov, M.R., ed. Interaction of ultrasound and
biological tissues, Washington, DC, US DHEW, pp. 141-152. (HEW
Publ. (FDA) 73-8008).

LEHMANN, J.F. & HERRICK, J.F. (1953) Biologic reactions to
cavitation, a consideration for ultrasonic therapy. Arch.
Phys. Med., 34: 86-98.

LEHMANN, J.F., McMILLAN, J.A., BRUNNER, G.D., & BLUMBERG,
J.B. (1959) Comparative study of the efficiency of
shortwave, microwave and ultrasonic diathermy in heating the
hip joint. Arch. Phys. Med., 40: 510-512.

LEHMANN, J.F., DeLATEUR, B.J., STONEBRIDGE, J.B., & WARREN,
C.G. (1967) Therapeutic temperature distribution produced by
ultrasound as modified by dosage and volume of tissue exposed.
Arch. Phys. Med., 48(12): 662-666.

LEHMANN, J.F., WARREN, C.G., & SCHAM, S.M. (1974)
Therapeutic heat and cold. In: Urist, M.R., ed. Clinical
orthopaedics and related research, Toronto, Lippincott
Company, pp. 207-245.

LEHMANN, J.F., WARREN, C.G., & GUY, A.W. (1978) Therapy with
continuing wave ultrasound. In: Fry, F.J., ed. Ultrasound: Its
application in medicine and biology, Amsterdam, Elsevier
Press, pp. 561-587.

LELE, P.P. (1967) Production of deep focal lesions by
focused ultrasound - current status. Ultrasonics, 5: 105-112.

LELE, P.P. (1975) Ultrasonic teratology in mice and man. In:
Proceedings of the Second European Congress of Ultrasonics in
Medicine, Munich, 12-16 May, Amsterdam, Excerpta Medica, pp.
22-27.

LELE, P.P. & PIERCE, A.D. (1972) The thermal hypothesis of
the mechanism of ultrasonic focal destruction in organized
tissues. In: Interaction of ultrasound and biological tissues,
Washington, DC, US DHEW, pp. 121-128 (HEW Publ. (FDA) 73-8008).

LEMONS, R.A. & QUATE, C.F. (1975) Acoustic microscopy - a
tool for medical and biological research, New York, Plenum
Press, pp. 305-317.

LERNER, R., CARSTENSEN, E., & DUNN, F. (1973) Frequency
dependence of thresholds for ultrasonic production of thermal
lesions in tissue. J. Acoust. Soc. Am., 54: 504-506.

LEVERETT, L.B., HELLUMS, J.D., ALFREY, C.P., & LYNCH, E.C.
(1972) Red blood cell damage by shear stress. Biophys. J.,
12: 257-273.

LEWIN, P.A. (1978) Ultrasound-induced damage of biological
tissue. PhD Thesis, AFM 78-16, Copenhagen, Technical
University of Denmark.

LEWIN, P.A. (1981a) Calibration and performance evaluation of
miniature ultrasonic hydrophone using time delay spectrometry.
In: Proceedings of the IEEE Ultrasonics Symposium, October
1981, pp. 660-664.

LEWIN, P.A. (1981b) Miniature piezoelectric polymer
ultrasonic hydrophone probes. Ultrasonics, 19: 213-216.

LEWIN, P.A. & CHIVERS, R.C. (1980) On viscoelastic models of
the cell membrane. Acoust. Lett., 4(5): 85-89.

LI, G.C., HAHN, G.M., & TOLMACH, L.J. (1977) Cellular
inactivation by ultrasound. Nature (Lond.), 267: 163-165.

LIEBESKIND, D., BASES, R., ELEQUIN, F., NEUBORT, S., LEIFER,
R., GOLDBERG, R., & KOENIGSBERG, M. (1979a) Diagnostic
ultrasound: effects on the DNA and growth patterns of animal
cells. Radiology, 131: 177-184.

LIEBESKIND, D., BASES, R., MENDEZ, F., ELEQUIN, F., &
KOENIGSBERG, M. (1979b) Sister chromatid exchanges in human
lymphocytes after exposure to diagnostic ultrasound. Science,
205: 1273-1275.

LIEBESKIND, D., BASES, R., KOENIGSBERG, M., KOSS, L., &
RAVENTOS, C. (1981a) Morphological changes in the surface
characteristics of cultured cells after exposure to diagnostic
ultrasound. Radiology, 138: 419-423.

LIEBESKIND, D., PADAWER, J., WOLLEY, R., & BASES, R. (1981b)
Diagnostic ultrasound: Time-lapse and transmission electron
microscopic studies of cells insonated in vitro. Presented at
the L.H. Gray Conference in Oxford, England, July 13-16. New
York, Albert Einstein College of Medicine.

LINDSTROM, K. & SVEDMAN, P. (1981) Ultrasound real-time
scanner used in air for imaging objects in the ambient
environment. IRCS med. Sci. biomed. Technol., 9: 132.

LINDSTROM, K. MAURITZSON, L., BENONI, G., SVEDMAN, P., &
WILLNER, S. (1982) Application of air-borne ultrasound to
biomedical measurements. Med. biol. Eng. Comput., 20: 392-400.

LIZZI, F.L., COLEMAN, D.J., DRILLER, J., FRANZEN, L.A., &
JAKOBIEC, F.A. (1978a) Experimental ultrasonically induced
lesions in the retina, choroid and sclera. Invest. Ophthalmol.
Visual Sci., 17(4): 350-360.

LIZZI, F.L., PACKER, A.J., & COLEMAN, D.J. (1978b)
Experimental cataract production by high frequency ultrasound.
Ann. Ophthalmol., 10: 934-942.

LONGO, F.W., TOMASHEFSKY, P., RIVEN, B.D., LONGO, W.E.,
LATTIMER, J.K., & TENNENBAUM, M. (1979) Interaction of
ultrasound with neoplastic tissue. Local effect on
subcutaneously implanted Furth-Columbia rat Wilm's tumor.
Urology, VI: 631-634.

LOTA, M.J. & DARLING, R.C. (1955) Changes in permeability of
red blood cell membrane in a homogeneous ultrasonic field.
Arch. phys. Med. Rehabil., 36: 282-287.

LOVE, L.A. & KREMKAU, F.W. (1980) Intracellular temperature
distribution produced by ultrasound. J. Acoust. Soc. Am., 67:
1045-1050.

LUK, K.H., HULSE, R.M., & PHILLIPS, T.L. (1980) Hyperthermia
in cancer therapy. Western J. Med., 132: 179-185.

LUNAN, K.D., WEN, A.C., BARFOD, E.T., EDMONDS, P.D., & PRATT,
D.E. (1979) Decreased aggregation of mouse platelets after
in vivo exposures to ultrasound. Thromb. Haemos., 40: 568-570.

LYNNWORTH, L.C. (1975) Industrial applications of ultrasound
- a review. II. Measurements, tests and process control using
low intensity ultrasound. IEEE Trans. Son. Ultrason.,
SU-22(2): 71-101.

LYON, M.F. & SIMPSON, G.W. (1974) An investigation into the
possible genetic hazards of ultrasound. Br. J. Radiol., 47:
712-722.

LYONS, E.A. (1982) Clinical applications of diagnostic
ultrasound. In: Repacholi, M.H. & Benwell, D.A., ed.
Essentials of medical ultrasound, New Jersey, Humana Press,
pp. 141-180.

LYONS, E.A. & COGGRAVES, M. (1979) Follow-up study in
children exposed to ultrasound in utero - an interim report.
Abstract. American Institute of Ultrasound in Medicine
Meeting, Montreal.

MacINTOSH, I.J.C. & DAVEY, D.A. (1970) Chromosome
aberrations induced by an ultrasonic fetal pulse detector.
Br. med. J., 4: 92-93.

MacINTOSH, I.J.C. & DAVEY, D.A. (1972) Relationship between
intensity of ultrasound and induction of chromosome
aberrations. Br. J. Radiol., 45: 320-327.

MacINTOSH, I.J.C., BROWN, R.C., & COAKLEY, W.T. (1975)
Ultrasound and in vitro chromosome aberrations. Br. J.
Radiol., 48: 230-232.

McCLAIN, R.M., HOAR, R.M., & SALTZMAN, M.B. (1972)
Teratologic study of rats exposed to ultrasound. Am. J.
Obstet. Gynecol., 114: 39-42.

MAEDA, K. & MURAO, F. (1977) Studies on the influence of
ultrasound irradiation on the growth of cultured cell in
vitro. In: White, D. & Brown, R.E., ed. Ultrasound in
medicine, New York, Plenum Press, Vol 3B, pp. 2045-2049.

MAJEWSKI, C., KALINOWSKI, M., & JANKOWIAK, J. (1966)
Electron-microscopic studies of acid phosphatase activity in
the liver of rats subjected to ultrasound. Am. J. phys. Med.,
45(5): 234-237.

MANLEY, D.M.J.P. (1969) Ultrasonic detection of gas bubbles
in blood. Ultrasonics, 7: 102-105.

MARMOR, J.B., MILERIC, F.J., & HAHN, G.M. (1979) Tumour
eradication and cell survival after localized hyperthermia
induced by ultrasound. Cancer Res., 39: 2166-2171.

MARMUR, R.K. & PLEVINSKIS, V.P. (1978) [Ultrasonic effects
of various intensities on manifestations and duration of
poststimulatory cytochemical changes in the retina.]
Oftalmol. Z., 33(4): 287-290 (in Russian).

MARTIN, C.J., GIMMELL, H.G., & WATMOUGH, D.J. (1978) A study
of streaming in plant tissue induced by a Doppler fetal heart
detector. Ultrasound Med. Biol., 4: 131-138.

MARTIN, C.J., GREGORY, D.W., & HODGEKISS, M. (1981) The
effects of ultrasound in vivo on mouse liver in contact with
an aqueous coupling medium. Ultrasound Med. Biol., 7(3):
253-265.

MARTINS, B.I. (1971) A study of the effects of ultrasonic
waves on reproductive integrity of mammalian cells cultures in
vitro. PhD Thesis, University of California (AEC Contract No.
W-7405-ang-48 Publ. LBL-37).

MASON, W.P. (1976) Sonics and ultrasonics: early history and
applications. In: Ultrasonics Symposium Proceedings,
pp. 610-617.

MERINO, O.R., PETERS, L.J., MASON, K.A., & WITHERS, H.R.
(1978) The effect of hyperthermia on the radiation response
of mouse jejunum. Int. J. Radiat. Oncol. Biol. Phys., 4:
407-414.

MICHAEL, P.L., HERMAN, R.L., BIENVENUE, G.R., & PROUT, H.
(1974) An evaluation of industrial acoustic radiation above
10 kHz, Washington, DC, US DHEW (US Dept HEW Publ. (HSM)
99-72-125).

MILLER, D.L., NYBORG, W.L., & WHITCOMB, C.C. (1979) Platelet
aggregation induced by ultrasound under specialized conditions
in vitro. Science, 205(3): 505-507.

MILLER, J.C., LEITH, J.T., VEOMETT, R.C., & GERNER, E.W.
(1976b) Potentiation of radiation myelitis in rats by
hyperthermia. Br. J. Radiol., 49: 895-896.

MILLER, M.W., KAUFMAN, G.E., CATALDO, F.L., & CARSTENSEN,
E.L. (1976a) Absence of mitotic reduction in regenerating
rat liver exposed to ultrasound. J. clin. Ultrasound, 4:
169-172.

MILLER, M.W., CIARAVINO, V., & KAUFMAN, G.E. (1977) Colony
size and giant cell formation from mammalian cells exposed to
1 MHz ultrasound radiation. Radiat. Res., 71: 628-634.

MILLER, W.F., JOHNSTON, F.F., & TARKOFF, M.P. (1968) Use of
ultrasonic aerosols with ventilatory assisters. J. Asthma
Res., 5: 335-354.

MOISEEVA, N.N. & GAVRILOV, L.R. (1977) [The influence of
focused high frequency ultrasound on eye tissues.] Oftalmol.
V., 32(3): 610-613 (in Russian).

MOLINARI, G.A. (1968a) [Low intensity ultrasound irradiation
of the cochlea through the round window: 1. Changes of
microphonic potentials]. Bull. Soc. Ital. Biol. Sper., 44:
403-406 (Canadian Govt. Trans. from Italian).

MOLINARI, G.A. (1968b) Low intensity ultrasound irradiation
of the cochlea through the round window: II. Changes in the
action potentials. Boll. Soc. Ital. Biol. Sper., 44: 406-408
(in Italian).

MOLLER, P. & GREVSTAD, A.O., & KRISTOFFERSEN, T. (1976)
Ultrasonic scaling of maxillary teeth causing tinnitus and
temporary hearing shifts. J. clin. Peridontol., 3: 123-127.

MOORE, J.L. & COAKLEY, W.T. (1977) Ultrasonic treatment of
Chinese hamster cells at high intensities and long exposure
times. Br. J. Radiol., 50: 46-50.

MOORE, R.M., BARRICK, M.K., & HAMILTON, P.M. (1982) Effects
of sonic radiation on growth and development. Am. J.
Epidemiol., 116(3): 571 (abstract).

MOROHASHI, T. & IIZUKA, R. (1977) Symposium on recent studies
in the safety of diagnostic ultrasound. The development of low
power ultrasonic instruments. Jpn. J. med. Ultrasound, 4:
271-273.

MORRIS, S.M., PALMER, C.G., FRY, F.J., & JOHNSON, L.K.
(1978) Effect of ultrasound on human leucocytes. Sister
chromatid exchange analysis. Ultrasound Med. Biol., 4: 253-258.

MORTIMER, A.J., ROY, O.Z., TAICHMAN, G.C., KEON, W.J., &
TROLLOPE, B.J. (1978) The effects of ultrasound on the
mechanical properties of rat cardiac muscle. Ultrasonics,
16(4): 179-182.

MOSKOW, B. & BRESSMAN, B. (1964) Cemental response to
ultrasonic and hand instrumentation. J. Am. Dent. Assoc., 68:
698-703.

MUIR, T.G. & CARSTENSEN, E.L. (1980) Prediction of
non-linear acoustic effects at biomedical frequencies and
intensities. Ultrasound Med. Biol., 6: 345-357.

MUKUBOH, M., OKAI, T., UEZUMA, S., BABA, K., MINOURA, S.,
KUMAGAI, K., HARA, K., & SAKAMOTO, S. (1981) [The safety and
irradiation effect of ultrasonic real time scanner on fetal
development.] Nippon Choompa Igakkai Koen-Rombunshu, 38:
555-556 (in Japanese).

MUMMERY, C.L. (1978) Effect of ultrasound on fibroblasts in
vitro. PhD Thesis, University of London.

MURAI, N., HOSHI, K., & NAKAMURA, T. (1975a) Effects of
diagnostic ultrasound irradiated during fetal stage of
development on orienting behaviour and reflex ontogeny in
rats. Tohoku J. exp. Med., 116: 17-24.

MURAI, N., HOSHI, K., KANG, C.-H., & SUZUKI, M. (1975b)
Effects of diagnostic ultrasound irradiated during fetal stage
on emotional and cognitive behaviour in rats. Tohoku, J. exp.
Med., 117: 225-235.

NATIONAL BUREAU OF STANDARDS (USA) (1973) Developing
ultrasound standards for use in medicine, industry, research.
Noise Control Rep., 2(15): 148.

NEPPIRAS, E.A. (1980) Acoustic cavitation threshold and
cyclic processes. Ultrasonics, 18(5): 201-209.

NEVARIL, C.G., LYNCH, E.C., ALFREY, C.R. Jr, & HELLUMS, J.D.
(1968) Erythrocyte damage and destruction induced by shear
stress. J. lab. clin. Med., 71: 784-790.

NORTHERN, J.L., DOWN, M.P., RUDMOSE, W., GLORIG, A., &
FLETCHER, J.L. (1962) Recommended high frequency audiometric
threshold levels (8000-18 000 Hz). J. Acoust. Soc. Am., 52:
585-595.

NYBORG, W.L. (1977) Physical mechanisms for biological
effects ultrasound, Washington DC, US DHEW (US Dept. HEW Pub.
(FDA), 78-8062).

NYBORG, W.L. (1978) Physical principles of ultrasound. In:
Fry, F.J., ed. Methods and phenomena 3, Ultrasound: Its
applications in medicine and biology, Part I, Amsterdam,
Elsevier Scientific Publishing Co., pp.1-75.

NYBORG, W.L. (1979) Physical mechanisms for biological
effects of ultrasound. In: Repacholi, M.H. & Benwell, D.A.,
ed. Ultrasound short course transactions 1979, Health and
Welfare, Canada, pp. 83-126.

NYBORG, W.L. (1982) Biophysical mechanisms of ultrasound. In:
Repacholi, M.H. & Benwell, D.A., ed. Essentials of medical
ultrasound, New Jersey, Humana Press, pp. 35-75.

NYBORG, W.L. & DYER, H.W. (1960) Ultrasonically induced
motions in single plant cells. In: Proceedings of the 2nd
International Conference on Medical Electronics, pp. 391-396.

NYBORG, W.L., MILLER, D.L., & GERSHOY, A. (1975) Physical
consequences of ultrasound on plant tissues and other
bio-systems. In: Michaelson, S.M., Miller, M.W., Magin, R., &
Carstensen, E.L., ed. Fundamental and applied aspects of
non-ionizing radiation, New York and London, Plenum Press, pp.
277-299.

O'BRIEN, W.D. Jr (1976) Ultrasonically induced fetal weight
reduction in mice. In: Ultrasound in medicine, New York,
Plenum Press, pp. 531-532.

O'BRIEN, W.D. (1978) Ultrasonic dosimetry. In: Fry, F.J., ed.
Methods and phenomena - ultrasound: Its applications in
medicine and biology, Part II, Amsterdam, Elsevier Scientific
Pub. Co.

O'BRIEN, W.D. & DUNN, F. (1972) Ultrasonic absorption
mechanisms in aqueous solutions of bovine hemoglobin. J. Phys.
Chem., 76(4): 528-533.

O'BRIEN, W.D., BRADY, J.K., & DUNN, F. (1979) Morphological
changes to mouse testicular tissue from in vivo ultrasonic
irradiation (preliminary report). Ultrasound Med. Biol., 5:
35-43.

PALZER, R.J. & HEIDELBURGER, C. (1973) Influence of drugs
and synchrony on the hyperthermic killing of Hela cells.
Cancer Res., 33: 422-427.

PARRACK, H.O. (1966) Effect of airborne ultrasound on humans.
Int. Aud., 5: 294-308.

PAYTON, O.D., LAMB, R.L., & KASEY, M.E. (1975) Effects of
therapeutic ultrasound on bone marrow in dogs. Phys. Ther.,
55(1): 20-27.

PIERSOL, G.M., SCHWAN, H.P., PENNELL, R.B., & CARSTENSEN, E.L.
(1952) Mechanism of absorption of ultrasonic energy in blood.
Arch. Phys. Med., 33: 327.

PINAMONTI, S., GALLENGA, P.E., & MAZZEO, V. (1982) Effect of
pulsed ultrasound on human erythrocytes in vitro. Ultrasound
Med. Biol., 8(6): (in press).

PINCUK, V.G., HEKLMAN, B.S., & LAZARETNYK, A. (1971)
[Ultrastructural changes in the kidney under the effect of
ultrasound.] Fiziol., 17: l09-113 (In Ukranian).

PIZZARELLO, D.J., WOLSKY, A., BECKER, M.H., & KEEGAN, A.F.
(1975) A new approach to testing the effect of ultrasound on
tissue growth and differentiation. Oncology, 31: 226-232.

POND, J. & DYSON, M. (1967) A device for the study of the
effects of ultrasound in tissue growth in rabbits' ears.
J. Sci. Instru., 44: 165-6.

POWELL-PHILLIPS, W.D. & TOWELL, M.E. (1979) Doppler
ultrasound and subjective assessment of fetal activity.
Br. med. J., 2: 101-102.

PREISOVA, J., HRAZDIRA, I., & DOLEMEK, A. (1965) The
influence of ultrasound on the surface temperature of the eye.
Ser. Med. (Fac. Med. Brun.), 38(5): 215-222.

REPACHOLI, M.H. (1969) The electrophoretic mobility of
tumour cells exposed to ultrasound and X-rays. MSc Thesis,
University of London.

REPACHOLI, M.H. (1970) Electrophoretic mobility of tumour
cells exposed to ultrasound and ionizing radiation. Nature
(Lond.), 227: 166-167.

REPACHOLI, M.H. (1980) The effect of ultrasound on human
lymphocytes: a search for dominant mechanisms of ultrasound
action. PhD Thesis, University of Ottawa.

REPACHOLI, M.H. (1981) Ultrasound: Characteristics and
biological action, National Research Council of Canada,
Ottawa, pp. 284, (Pub. NRCC 19244).

REPACHOLI, M.H. & BENWELL, D.A. (1979) Using surveys of
ultrasound therapy devices to draft performance standards.
Health Phys., 36: 679-686.

REPACHOLI, M.H., & BENWELL, D.A. (1982) Ultrasound standards:
regulations and guidelines. In: Repacholi M.H. & Benwell,
D.A., ed. Essentials of medical ultrasound, New Jersey, Humana
Press, pp. 281-304.

REPACHOLI, M.H., & KAPLAN, J.C. (1980) DNA repair synthesis
observed in human lymphocytes exposed in vitro to therapeutic
ultrasound. In: Proceedings of the American Institute of
Ultrasound in Medicine Convention, New Orleans, Sept. 15-19,
p.42.

REPACHOLI, M.H., WOODCOCK, J.P., NEWMAN, D.L., & TAYLOR,
K.J.W. (1971) Interaction of low intensity ultrasound and
ionizing radiation with the tumour cell surface. Phys. Med.
Biol., 16: 221-226.

REPACHOLI, M.H., KAPLAN, J.G., & LITTLE, J. (1979) The
effect of therapeutic ultrasound on the DNA of human
lymphocytes. In: Kaplan, J.G., ed. The molecular basis of
immune cell function, Amsterdam, Elsevier/North Holland
Biomedical Press, pp. 443-446.

REZNIKOFF, C.A., BERTRAM, J.S., BRANKOW, D.W., & HEIDELBERGER,
C. (1973) Quantitive and qualitative studies of chemical
transformation of cloned C3H mouse embryo cells sensitive to
post confluence inhibition of cell division. Cancer Res., 33:
3239-3249.

ROBINSON, R.A. (1977) Radiation force techniques for
laboratory and field measurement of ultrasonic power. In:
Symposium on Biological Effects and Characterizations of
Ultrasound Sources, Washington, DC, US DHEW, pp. 114-124 (HEW
Pub. (FDA 78-8048)).

ROMAN, M.P. (1960) A clinical evaluation of ultrasound by use
of a placebo technique. Phys. Ther. Rev., 40(9): 649-652.

ROONEY, J.A. (1970) Hemolysis near an ultrasonically pulsating
gas bubble. Science, 169: 869-871.

ROONEY, J.A. (1973) Determination of acoustic power outputs
in the microwatt-milliwatt range. Ultrasound Med. Biol., l:
l3-l6.

ROONEY, J.A. (1981) Nonlinear phenomena. In: Edmonds, P.,
ed. Methods of experimental physics - ultrasonics, New York,
London, Toronto, Sydney and San Francisco, Academic Press,
Vol. 19, pp. 299-353.

ROTT, H.D. & SOLDNER, R. (1973) The effect of ultrasound on
human chromosomes in vitro. Humangenetik, 20: 103-112.

SAAD, A.H. & WILLIAMS, A.R. (1982) The effects of ultrasound
upon the rate of clearance of blood-borne sulphur colloid in
vivo. Br. J. Cancer, 45: 202-205.

SALCMAN, M. (1981) Clinical hyperthermia trials: Design
principles and practice. J. Microwave Power, 16(2): 171-177.

SAMOSUDOVA, N.V. & EL'PINER, I.Y. (1966) Ultrastructure of
myofibrils exposed to ultrasonic waves. Biofizika, 11(4):
713-715.

SARVAZYAN, A.P., BELOUSOV, L.V., PETROPAVLOVSKAYA, M.N., &
OSTROUMOVA, T.V. (1980) The interaction of low intensity
ultrasound with developing embryos. In: Ultrasound Interaction
in Biology and Medicine. International Symposium, Nov. 10-14,
Castle-Reinhardsbrunn GDR, p. C-18.

SCHEIDT, P.C., STANLEY, F., & BRYLAS, D.A. (1978) One year
follow-up of infants exposed to ultrasound in utero. Am. J.
Obstet. Gynecol., 131(7): 743-748.

SCHMITZ, W. (1950) [Ultrasound as a means of protection.]
Strahlentherapie, 83: 654-662 (in German).

SCHNITZLER, R.M. (1972) Ultrasonic effects on mitosis - a
review. In: Reid, J.W. & Sikov, M.R., ed. Interaction of
ultrasound and biological tissues, Washington, DC, US DHEW,
pp. 69-72 (US Dept HEW Pub. (FDA) 73-8008).

SEKIBA, K., KAWAI, J., AKAMATSU, N., OBATA, A., NIWA, K., &
UTSUMI, K. (1980) Ultrasound irradiation effects on embryos
(9). Effects of continuous wave on rat embryo (2). Nippon
Choompa Igakkai, Koen-Rombunshu, 37:157-158.

SELMAN, G.G. & COUNCE, S.J. (1953) Abnormal embryonic
development in Drosophila induced by ultrasonic treatment.
Nature (Lond.), 172: 503-504.

SELMAN, G.G. & JURAND, A. (1964) An electron microscope study
of the endoplasmic reticulum in the notochord cells after
disturbance with ultrasound treatment and subsequent
regeneration. J. cell Biol., 2O: l75-l83.

SERR, D.M., PADEH, B., ZAKUT, H., SHAKI, R., MANNOR, S.M., &
KALNER, B. (l97l) Studies on the effects of ultrasonic waves
on the fetus. In: Hungerford, P.J., ed. Proceedings of the
2nd European Congress Prenatal Medicine, Basel, Karger, pp.
3O2-3O7.

SHIMIZU, T. (1977) Special issue on the present status of
safety studies on ultrasonic diagnosis in obstetrics: basic
studies on the biological action of ultrasound. Jpn. J. med.
Ultrason., 4: 264-266.

SHIMIZU, T. & SHOJI, R. (1973) An experimental study of mice
exposed to low intensity ultrasound, Sapporo, Japan Zoological
Inst., Kokkaido Univ.

SHIMIZU, T. & TANAKA, K. (1980) Experimental teratology of
ultrasound exposure in animals. The 1979 report on the
research grant of the prevention of physical and mental
disabilities, Tokyo, Ministry of Health and Welfare, Japanese
Government, 171-176.

SHIRAISHI, Y. & SANDBERG, A.A. (1980) Sister chromatid
exchange in human chromosomes, including observations in
neoplasia. Canc. Genet. Cytogenet., 1: 363-380.

SHOH, A. (1975) Industrial applications of ultrasound - a
review. I. High power ultrasound, IEEE Trans. Son. Ultrason.,
SU-22(2): 60-71.

SHOJI, R. MOMMA, E., SHIMIZU, T., & MATSUDA, S. (1971) An
experimental study on the effects of low-intensity ultrasound
on developing mouse embryos. J. Fac. Sci. Hokkaido Univ.,
Series VI, 18(1): 51-56.

SHOJI, R. MURAKAMI, U., & SHIMIZU, T. (1975) Influence of low
intensity ultrasonic irradiation on prenatal development of
two inbred mouse strains. Teratology, 12: 227-232.

SHOTTON; R.C. (1980) A tethered float radiometer for
measuring the output power from ultrasonic therapy equipment.
Ultrasound Med. Biol., 6: 131.

SHOTTON, R.C., BACON; D.R., & QUILLIAM, R.M. (1980) A PVDF
membrane hydrophone for operation in the 0.5 MHz to 15 MHz.
Ultrasonics, 18: 123-126.

SHUBA, E.P., BOLITSKY, K.P., PANFILOVA, T.K., & BARAN, L.A.
(1976) Combined action of X-ray radiation and ultrasound on
the growth of experimental tumours. Med. Radiol., 21: 42-47.

SIEGEL, E., GODDARD, J., JAMES, A.E., & SIEGEL, M.S. (1979)
Cellular attachment as a sensitive indicator of the effects of
diagnostic ultrasound on cultured human cells. Radiology, 133:
175-179.

SIKOV, M.R. & HILDEBRAND, B.P. (1977) Embryotoxicity of
ultrasound exposure at nine days of gestation in the rat. In:
White, D. & Brown, R.E., ed. Ultrasound in medicine, New York,
Plenum Press, Vol. 3B, pp. 2009-2016.

SIKOV, M.R., HILDEBRAND, B.P., & STERNS, J.D. (1976) Effects
of exposure of the nine-day rat embryo to ultrasound. In:
White, D. & Barnes, R., ed. Ultrasound in medicine, New York
and London, Plenum Press, Vol. 2, pp. 529-538.

SIKOV, M.R., HILDEBRAND, B.P., & STERNS, J.D. (1977)
Postnatal sequelae of ultrasound exposure at 15 days of
gestation in the rat. (Work in progress). In: White, D. &
Barnes, R., ed. Ultrasound in medicine, Vol 3B, pp. 2017-2023.

SILVERMAN, C. (1973) Nervous and behavioural effects of
microwave radiation in humans. J. Epidemiol. 97: 219-224.

SKILLERN, C.P. (1965) Human response to measured sound
pressure levels from ultrasonic devices. Ind. Hyg. J., 26:
132-136

SLAWKINSKI, P. (1965) [The effect of ultrasound on the
metabolsm of iodine in guinea pigs.] Rocz. Pomor. Akad. Med.
(zen Karola Swierczewskiego), 11: 259-282 (in Polish).

SLAWKINSKI, P. (1966) [Histologic studies on the thyroid
gland in guinea pigs subjected to the action of ultrasound.]
Patol. Pol., 17(2): 147-154 (in Polish).

SLOTOVA, J., KARPFEL, Z., & HRAZDIRA, I. (1967) [Chromosome
aberrations caused by the effect of ultrasound in the
meristematic cells of Vicia Faba.] Biol. Plantarum (Praha),
9(1): 49-55 (in Czech).

SMACHLO, K., FRIDD, C.W., CHILD, S.Z., HARE, J.D., LINKE,
C.A., & CARSTENSEN, E.L. (1979) Ultrasonic treatment of
tumors: l. Absence of metastases following treatment of a
hamster fibrosarcoma. Ultrasound Med. Biol., 5(1): 45-49.

SMITH, P.E. (1967) Temporary threshold shift produced by
exposure to high frequency noise. Am. Ind. Hyg. Assoc. J., 28:
447.

SORENSEN, H., & ANDERSEN, M.S. (1976) The effect of
ultrasound in Ménière's disease. Acta Otolaryngol., 82:
312-315.

STANDARDS ASSOCIATION OF AUSTRALIA (1969) Ultrasonic therapy
equipment, Sydney, Standards Assoc. of Australia (Pub.
AST40-1969).

STEPHENS, R.H., TORBIT, C.A., GROTH, D.G., TAENZER, J.C., &
EDMONDS, P.D. (1978) Mitochondrial changes resulting from
ultrasound irradiation. In: White, D. & Lyons, E.A. ed.
Ultrasound in medicine, New York, Plenum Press, Vol. 4, pp.
591-594.

STEPHENSON, S.R. & WEAVER, D.D. (1981) Prenatal Diagnosis: A
compilation of diagnosed conditions. Am. J. Obstet. Gynecol.,
141(3): 319-343.

STEREWA, S. (1977) Effect of ultrasonic energy on the level
of thyronins in the blood serum, Biofizika, 22(4): 659-662.

STEREWA, S. & BELEWA-STAIKOVA, R. (1976) Influence of
ultrasonic energy on the level of the thyronins in the thyroid
gland. Folia Med., 18(2): 155-159.

STETKA, D.G. & WOLFF, S. (1977) Sister chromatid exchanges as
an assay for genetic damage induced by mutagen-carcinogens. I.
In vivo test for compounds requiring metabolic activation.
Mutation Res., 41: 333-342.

STEWART, H.F. (1975) Ultrasonic measuring techniques. In:
Michaelson, S.M., Miller, M.W., Magin, R., & Carstensen, E.L.,
ed. Fundamental and applied aspects of non-ionizing radiation,
New York and London, Plenum Press, pp. 59-89.

STEWART, H.F. (1979) Diagnostic ultrasonic output levels and
quality assurance measurements. In: Proceedings of the
Eleventh Annual National Conference on Radiation Control,
Oklahoma City, OK, May 6-10, Washington, DC, US Government
Printing Office.

STEWART, H.F. (1982) Ultrasonic measurement techniques and
equipment output levels. In: Repacholi, M.H. & Benwell, D.A.,
ed. Essentials of medical ultrasound, New Jersey, Humana
Press, pp. 77-116.

STEWART, H.F. & STRATMEYER, M.E. (1982) An overview of
ultrasound: Theory, measurement, medical applications and
biological effects, Washington, DC, US Dept of Health and
Human Services (DHEW Pub. (FDA) 82-8190).

STEWART, H.F. ABZUG, J.L., & HARRIS, J. (1980) Considerations
in ultrasound therapy and equipment performance. Phys. Ther.,
60(4): 424-428.

STEWART, H.F., REPACHOLI, M.H., & BENWELL, D.A. (1982)
Ultrasound Therapy, In: Repacholi, M.H. & BENWELL, D.A.,
Essentials of medical ultrasound, New Jersey, Humana Press,
pp. 181-213.

STOLZENBERG, S.J., TORBIT, C.A., EDMONDS, P.D., TAENZER, J.C.
NELL, D.P., MADAN, S.M., MARKS, D.O., & PRATT, D.E. (1978)
Effects of continuous wave ultrasound on the mouse at
different stages of gestation. J. Acoust. Soc. Fam., 63
(Suppl. No. 1): S27.

STOLZENBERG, S.J., TORBIT, C.A., EDMONDS, P.D., & TAENZER,
J.C. (1980a) Effects of ultrasound on the mouse exposed at
different stages of gestation: acute studies. Radiat. Environ.
Biophys., 17: 245-270.

STOLZENBERG, S.J., TORBIT, C.A., PRYOR, G.T., & EDMONDS, P.D.
(1980b) Toxicity of ultrasound in mice: neonatal studies.
Radiat. environ. Biophys., 18: 37-44.

STOLZENBERG, S.J., EDMONDS, P.D., TORBIT, C.A., & SASMORE,
D.P. (1980c) Toxic effects of ultrasound in mice: damage to
central and autonomic nervous systems. Toxicol. appl.
Pharmocol., 53: 432-438.

STRABURZYNSKI, G., JENDYKIEWICS, Z., & SZULC. S. (1965)
[Effect of ultrasonics on glutathione and absorbic acid
contents in blood and tissues.] Acta Physiol. Pol., 16(5):
612-619 (in Polish).

STRATMEYER, M.E. (1977) Research directions in ultrasound
bioeffects - a public health view. In: Proceedings of a
Symposium on Biological Effects and Characterizations of
Ultrasound Sources, Rockville, MD, Washington, DC, US DHEW,
pp. 240-245 (DHEW Publ. FDA 78-8048).

STRATMEYER, M.E., SIMMONS, L.R., PINKAVITCH; F.Z., JESSUP,
G.L., & O'BRIEN, W.D. (1977) Growth and development of mice
exposed in utero to ultrasound. In: Hazzard, D.G. & Litz,
M.L., ed. Symposium on Biological Effects and Characterization
of Ultrasound Sources, Washington, DC, US DHEW, pp. 140-145
(DHEW Publ. (FDA) 78-8048).

STRATMEYER, M.E., SIMMONS, L.R., & PINKAVITCH, F.Z. (1979)
Effects of in utero ultrasound exposure on the growth and
development of mice. In: 2nd Meeting of the World Federation
of Ultrasound in Medicine and Biology, Miyazaki, Japan (July
22-27, 1979), Tokyo, Scimed Publications, p. 417.

STRATMEYER, M.E., PINKAVITCH, F.Z., SIMMONS, L.R., &
STERNTHAL, P. (1981) In utero effects of ultrasound exposure
in mice. In: American Institute of Ultrasound in Medicine
Meeting, San Francisco, CA, August 17-21, p. 121 (abstract).

STUMPFF, U., POHLMAN, R., & TRBENSTEIN, G. (1975) A new
method to cure thrombi by ultrasonic cavitation. In:
Ultrasonics International 1975, Guildford, IPC Science and
Technology Press, pp. 273-275.

SUTHERLAND, R.P. & VERRALL, R.E. (1978) High Energy
ultrasound effect on biological systems, Regina, Saskatchewan,
(Report presented to M.C.I.C., Government of Saskatchewan,
Canada, March 8).

SWEDEN (1978) [Infra and ultrasound in occupational life.]
Vaellingby, Sweden, Liber Foerlag 162 89 (Pub. No. 110:1-1978
(ISBN 91-38-04082-4, ISBN 0491-7448)) (in Swedish).

TACHIBANA, M., TACHIBANA, Y., & SUZUKI, M. (1977) The present
status of the safety of ultrasonic diagnosis in the area of
obstetrics - the effect of ultrasound irradiation on pregnant
mice as indicated in their fetuses. Jpn. J. med. Ultrason., 4:
279-283.

TAKABAYASHI, T., ABE, Y., SATO, S., SATO, A., & SUZUKI, M.
(1980) Influence of pulse wave ultrasonic irradiation on
prenatal development of the mouse. Acta Gynaecol. Jpn., 31(7):
895-896.

TAKEMURA, H. & SUEHARA, N. (1977) Study on the hemolytic
effect of clinical diagnostic ultrasound and the growth rate
of cultured cells using a calibrated ultrasound generating
system. Jpn. J. med. Ultrason., 4: 284-288.

TAKEUCHI, H., ARIMA, M., & MIZUNO, S. (1966) Studies on the
ultrasonic irradiation of rat embryos. (2nd report). - Pulsed
ultrasound for diagnostic use. Med. Ultrason., 4: 20-21.

TAKEUCHI, H., KOBAYASHI, T., SUGIE, T., KAWAMETA, C., &
FURUYA, H. (1977) Survey of fetal ultrasonic diagnosis and
determination of ultrasonic intensity in the uterus. Jpn. J.
med. Ultrason., 4:267-270.

TALBERT, D.G. (1975) Spontaneous smooth muscle activity as a
means of detecting biological effects of ultrasound.
Proceedings Ultrasonics International, 1975, Guildford, I.P.C.
Science and Technology Press, pp. 279-284.

TALBOT, J.F., MARSHALL, J., SHERRARD, E., & KOHNER, E.M.
(1980) Experimental phacoemulsification: effects on the
corneal endothelium. In: Proceedings, European Congress of
Ophthalmology, Brighton.

TAYLOR, K.J. W. & POND, J.B. (1970) The effects of ultrasound
of varying frequencies on rat liver. J. Pathol., 100: 287-293.

TAYLOR, K.J.W. & POND, J.B. (1972) A study of the production
of haemorrhagic injury and paraplagia in rat spinal cord by
pulsed ultrasound of low megahertz frequencies in the context
of the safety for clinical usage. Br. J. Radiol., 45: 343-353.

TAYLOR, K.J.W. & NEWMAN, D.L. (1972) Electrophoretic mobility
of Ehrlich cell suspensions exposed to ultrasound of varying
parameters. Phys. Med. Biol., 17: 270-276.

TER HAAR, G.R. (1977) The effect of ultrasonic standing wave
fields on the flow of particles, PhD Thesis, University of
London.

TER HAAR, G.R. & DANIELS, S. (1981) Evidence for
ultrasonically induced cavitation in vivo. Phys. Med. Biol.,
26(6): 1145-1149.

TER HAAR, R.G., & WYNARD, J.S. (1978) Blood cell banding in
ultrasonic standing wave fields: a physical analysis.
Ultrasound Med. Biol., 4: 111-123.

TER HAAR, G.R., DYSON, M., & TALBERT, D. (1978)
Ultrasonically induced contractions in mouse uterine smooth
muscle in vivo. Ultrasonics, 16(6): 275-276.

TER HAAR, G.R., DYSON, M., & SMITH, S.P. (1979)
Ultrastructural changes in the mouse uterus brought about by
ultrasonic irradiation at therapeutic intensities in standing
wave fields. Ultrasound med. Biol., 5: 167-179.

TER HAAR, G.T., STRATFORD, I.J., & HILL, C.R. (1980)
Ultrasonic irradiation of mammalian cells in vitro at
hyperthermic temperatures. Br. J. Radiol., 53: 784-789.

THACKER, J., (1973) The possibility of genetic hazard from
ultrasonic radiation. Curr. Top. Radiat. Res. Q., 8: 235-258.

THACKER, J. (1974) An assessment of ultrasonic radiation
hazard using yeast genetic systems. Br. J. Radiol., 47:
130-138.

THACKER, J. & BAKER, N.V. (1976) The use of Drosophila to
estimate the possibility of genetic hazard from ultrasound
irradiations. Br. J. Radiol., 49: 367-371.

TODD, P. & SCHROY, C.B. (1974) X-ray inactivation of cultured
mammalian cells enhancement by ultrasound. Rad. Biol., 113:
445-447.

TORBIT, C.A., STOLZENBERG, S.J., & EDMONDS, P.D. (1978)
Inhibition of ovulation in female mice after ultrasonic
irradiation. In: Proceedings of 23 Annual Meeting of the
American Institute of Ultrasound in Medicine, San Diego,
California, Vol. I, p. 75 (abstract 1306).

TSUTSUMI, Y., SANO, K., KUWABARA, T., TAKAKURA, K., HAYAKAWA,
I., SUZUKI, T., & KATANUMA, M. (1964) A new portable
echo-encephlograph, using ultrasonic transducers; and its
clinical application. Med. Electron Biol. Eng., 2: 21-29.

US FOOD AND DRUG ADMINISTRATION (1978) Performance standard
for ultrasonic therapy products. Fed. Reg., 43(34): 7166-7172.

US AIR FORCE (1976) Hazardous Noise Exposure (AFR l6l-35)
United States Air Force Regulation, pp. 7-26.

USSR STATE COMMITTEE FOR STANDARDS (1975) USSR Health
Standards for Occupational Exposure, GOST 12.1.00l-75,
Ultrasound, Moscow, p.9.

VALTONEN, E.J. (1967) Influence of ultrasonic radiation in
the medical therapeutic range on the fine structure of the
liver parenchymal cell. V irchows Arch. Pathol. Anat. Physiol.,
343: 26-33.

VERESS, E. & VINEZE, J. (1976) The haemolysing action of
ultrasound on erythrocytes. Acustica, 36: 100-103.

VON GIERKE, H.E. (1950a) Subharmonics generated in the ears
of humans and animals at the intense sound levels. Am. Soc.
Exp. Biol. Fed. Proc., 9: l80.

VON GIERKE, H.E. (1950b) Subharmonics generated in human and
animal ears by intense sound. J. Acoust. Soc. Am., 22: 675.

WATMOUGH, D.J., DENDY, P.P., EASTWOOD, L.M., GREGORY, D.W.,
GORDON, F.C.A., & WHEATLEY, D.N. (1977) The biophysical
effects of therapeutic ultrasound on HeLa cells. Ultrasound
Med. Biol., 3: 205-219.

WATTS, P.L. & STEWART, C.R. (1972) The effect of fetal heart
monitoring by ultrasound on maternal and fetal chromosomes. J.
Obstet. Gynaecol. Br. Commonw., 79: 715-716.

WATTS, P.L., HALL, A.J., & FLEMING, J.E.E. (1972) Ultrasound
and chromosome damage. Br. J. Radiol., 45: 335-339.

WEBSTER, D.F., POND, J.B., DYSON, M., & HARVEY, W. (1978) The
role of cavitation on the in vitro stimulation of protein
synthesis in human fibroblasts by ultrasound. Ultrasound Med.
Biol., 4: 343-351.

WEGNER, R.D., OBE, G., & MEYENBURG, M. (1980) Has diagnostic
ultrasound mutagenic effects? Hum. Genet., 56: 95-98.

WELLS, P.N.T. (1977) Biomedical ultrasonics, London, Academic
Press.

WIEN, D.-D. & HARDER, D. (1982) Characteristics of the pulsed
ultrasound field. Br. J. Cancer, 45: 59-63.

WILKINSON, R.G. & MAYBURY, J.E. (1973) Scanning electron
microscopy of the root surface following instrumentation.
J. Periodontol., 44: 559.

WILLIAMS, A.R. (1972) Disorganization and disruption of
mammalian and amoeboid cells by acoustic microstreaming.
J. Acoust. Soc. Am., 52: 688-693.

WILLIAMS, A.R. (1974) Release of serotonin from human
platelets by acoustic microstreaming. J. Acoust. Soc. Am., 56:
1640-1643.

WILLIAMS, A.R. (1975) An ultrasonic technique to generate
intravascular microstreaming. Ultrasonics International 1975
Conference Proceedings, pp. 266-268.

WILLIAMS, A.R. (1977) Intravascular mural thrombi produced by
acoustic microstreaming. Ultrasound Med. Biol., 3: 191-203.

WILLIAMS, A.R. (1982a) Absence of meaningful thresholds for
bioeffect studies on cell suspensions in vitro. Br. J. Cancer,
45(Suppl. 5): 192-195.

WILLIAMS, A.R. (1982b) Biological effects of ultrasound,
London, Academic Press (in press).

WILLIAMS, A.R. & MILLER, D.L. (1980) Photometric detection
of ATP release from human erythrocytes exposed to
ultrasonically activated gas-filled pores. Ultrasound Med.
Biol., 6: 251-256.

WILLIAMS, A.R., HUGHES, D.E., & NYBORG, W.L. (1970) Hemolysis
near a transversely oscillating wire. Science, 169: 871-873.

WILLIAMS, A.R., O'BRIEN, W.D. Jr, & COLLER, B.S. (1976a)
Exposure to ultrasound decreases the recalcification time of
platelet rich plasma. Ultrasound Med. Biol., 2: 113-118.

WILLIAMS, A.R., SYKES, S.M., & O'BRIEN, W.D. Jr (1976b)
Ultrasonic exposure modifies platelet morphology and function
in vitro. Ultrasound Med. Biol., 2: 311-317.

WILLIAMS, A.R., CHATER, B.V., SANDERSON, J.H., TABERNER, D.A.,
MAY, S.A., ALLEN, K.A., & SHERWOOD, M.R. (1977)
Beta-thromboglobulin release from human platelets after in
vivo ultrasound irradiation. Lancet, 2: 931.

WILLIAMS, A.R., CHATER, B.V., ALLEN, K.A., SHERWOOD, M.R., &
SANDERSON, J.H. (1978) Release of Beta-thromboglobulin from
human plateletes by therapeutic intensities of ultrasound.
Br. J. Haematol., 40: 133-142.

WILLIAMS, A.R., CHATER, B.V., ALLEN, K.A., & SANDERSON, J.H.
(1981) The use of Beta-Thromboglobulin to detect platelet
damage by therapeutic ultrasound in vivo. J. clin. Ultrasound,
9: 145-151.

WILLIAMS, J.W. & HODGSON, W.J.B. (1979) Histological
evaluation of tissues sectioned by ultrasonically powered
instruments. Mt. Sinai J. Med. (NY), 46: 105-106.

WILSON, D.T.J., TANCRELL, R.H., & CALLERAME, J. (1979) PVF2
polymer microprobe. In: Fourth International Symposium on
Ultrasonic Imaging and Tissue Characterization, pp.39 and 41.

WITCOFSKI, R.F. & KREMKAU, F.W. (1978) Ultrasonic
enhancement of cancer radiotherapy. Radiology, 127: 793.

WOEBER, K. (1965) The effect of ultrasound in the treatment
of cancer. In: Kelly, E., ed. Ultrasonic energy. Illinois,
University of Illinois Press, pp. 147-149.

WONG, Y.S. & WATMOUGH, D.J., (1980) Haemolysis of red blood
cells in vitro and in vivo caused by therapeutic ultrasound at
0.75 MHz. In: Proceedings of the Ultrasound Interaction in
Biology and Medicine Symposium, Reinhardsbrunn, GDR, November
10-14 (Paper C-14).

YARONIENE, G. (1978) Response of biological systems to low
intensity ultrasonic waves. In: Second Congress of the
Federation of Acoustical Societies of Europe, pp.13-16,
Warszawa, Poland.

YEAS, J. & BARNES, F.S. (1970) An ultrasonic drill for
cleaning blood vessels. Biomed. Sci. Instrum., 7: 165-167.

ZAROD, A.P. & WILLIAMS, A.R. (1977) Platelet aggregation in
vivo by therapeutic ultrasound. Lancet, 1: 1266.

ZATULINA, N.I. & ARISTARKHOVA, A.A. (1974) [Ultrasound
produced cytological changes in the corneal epithelium.]
Vestn. Oftalmol., 4: 47-50 (in Russian).

ZEMANEK, J. (1971) Beam behaviour within the nearfield of
vibrating piston. J. Acoust. Soc. Am., 49(1): 181-191.

ZIENIUK, J.K. & CHIVERS, R.C. (1976) Measurement of
ultrasonic exposure with radiation force and thermal methods.
Ultrasonics, 14: 161-171.

ZISKIN, M.C., CONGER, A.D., WITTELS, H., & LAPAYOWKER, M.S.
(1980) Mammalian multicellular tumor spheroids: An
experimental model for ultrasonic bioeffects on cells. In:
Proceedings 25th Annual Meeting of the American Institute for
Ultrasound in Medicine, New Orleans, Sept. 15-19, p.41.

ZWEIFEL, H.J. (1979) [Relationship between investigator and
technology in ultrasound diagnosis.] In: Conference
Proceedings of the Three Country Meeting of Diagnostic
Ultrasound in Medicine. Davos, Switzerland, February 14-17,
1979, Stuttgart & New York, Georg Thieme Verlag. p. 246 (in
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 alpha_a m-1 Np/cm or dB/cm*
coefficient

Characteristic acoustic Z_o 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) I_p W/m² W/cm² or mW/cm²

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

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

Spatial peak - pulse I_SPPA 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 I_SPTA W/m² W/cm² or mW/cm²
average intensity

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

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

Particle acceleration a m/s²

Particle displacement xi m µm

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

Particle velocity
v = deltaxi /deltat = v_o cos (omegat - kx)
where v_o = deltaxi_o = velocity amplitude

Particle acceleration
a = delta v/delta t = -a_o sin (omegat - kx)
where a_o = omega²xi_o = acceleration amplitude

Acoustic pressure
deltap/deltax = -rho a, hence
P = P_o cos (omegat - kx)
P_o = rhoomega²xi_o/k = pressure amplitude
c = speed of sound

Energy density
The energy density of the sound field is
W = rho v_o²/2 or, using
Z_o = rho c, v_o = omegaxi_o, P_o = rhoomegaxi_o
W = rho P_o²/2 Z_o² = P_o²/2rho c²

Intensity
The average intensity (averaged over one cycle
of the wave) is given by
I_a = cW;
hence, using W = P_o²/2rho c²
I_a = P_o²/2rho c

For a given intensity, the quantities xi_o, v_o, a_o,
and P_o can be calculated from
xi_o = 1/omega(2 I_a/rho c)^0.5
v_o = (2 I_a/rho c)^0.5
a_o = omega(2 I_a/rho c)^0.5
P_o = (2rho cI_a)^0.5

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

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 ( I_p).
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 equipment^a
-----------------------------------------------------------------------------------
Therapeutic Diagnostic Ultrasound Diagnostic Ultrasound
Ultrasound Pulse Echo cw Doppler
I_a = 100-3000 I_a = 100-100 000 I_a = 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 10-³to
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 ( I_a): The intensity of the wave average
over one cycle. In such a wave the instantaneous peak intensity
(I_p) is twice the value of I_a, i.e. I_p = 2 I_a (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