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The objectives of the AIUM/NEMA safety standard and the IEC draft are similar and intended to ensure that sufficient information regarding output of diagnostic ultrasound instruments is available so that users can make informed judgements regarding equipment uses. The objectives of the IEC draft standard are to 1. (i) define a group of acoustic parameters which can be measured on a physically practical basis (hydrophones); 2. (ii) define a second group of parameters which can be derived under certain assumptions from these measurements and called derived intensity parameters; 3. (iii) define a measurement procedure which may be used for the determination of acoustic pressure parameters; 4. (iv) define the conditions under which the measurements of acoustic parameters can be made in the frequency range 0.5–15 MHz using calibrated piezoelectric hydrophones. Although a group of exposure parameters has been identified, the IEC does not recommend which is the most relevant for field characterisation. The difference between standards is largely a result of uncertainties in the use of hydrophones at the time of formulating the AIUM/NEMA standard. With the advent of modern high quality PVDF miniature hydrophones the more recent IEC Draft Standard recommends specification of the acoustic field in terms of acoustic pressure which is directly measured with a hydrophone. The IEC also differs from the AIUM/NEMA standard for acoustic labelling, where the quantity measured by miniature hydrophones is defined as acoustic pressure and prefers not to use intensity which is derived from plane wave approximation.

This paper presents a review of published standards and recommendations or policy statements that exist for equipment design and performance, and for limiting human exposure to ultrasound. Recommendations on research priorities identified by various institutions form the basis of a separate publication in this text by Dr. Nyborg. General guidelines or policy statements have been issued by various professional, national and international organisations and these will be described and discussed. Earlier reviews of standards and recommendations can be found in Repaeholi and Benwell (1982), IRPA/WHO (1982), NCRP (1983) and Nyborg and Ziskin (1985).

• Diagnostic levels of pulsed ultrasound were applied abdominally over the uteri of pregnant rats for five minutes daily during the first 20 days of gestation. The average energy output of the ultrasound machine at the optimum focal length of the transducer (5.4 cm) was 7.2 mW/sq cm. Postnatal auditory evoked potentials demonstrated a significant alteration in the offspring of the treated animals when compared with similarly treated, but nonexposed controls. This alteration only occurred in the high frequency range. Neither light nor electron microscopy revealed significant morphologic alterations in the cochlear elements of the exposed offspring. Although a cochlear deficit occurred in a range known to be important to the rat's hearing, several issues make this data reassuring to clinicians using diagnostic levels of pulsed ultrasound: the total amount of ultrasound exposure was higher than would be expected with human use, the defect was mild, and the absence of clear-cut morphologic abnormalities may indicate the presence of a minimal, or even reversible, defect. (Arch Otolaryngol1985;111:309-314)

In the last few years several reports have been published which include recommendations for research. One of these (BRH, 1982) is a publication of the U.S. Department of Health and Human Services, Bureau of Radiological Health (BRH), prepared by government scientists. The BRH report contains a comprehensive tabulation and discussion of literature on biological effects of ultrasound, especially where these bear on safety of medical ultrasound. On the basis of the literature survey, areas were identified in which further research is needed. The BRH report, including the research recommendations, was reviewed before publication by many individuals, within the government and outside. Their section entitled “Recommendations for further research” is here reproduced (essentially) verbatim.

A compilation of reports of biological effects and related ultrasound exposure levels can be useful in the identification of trends in effects data that may be developing in the literature. The exposures in the experiments reviewed were at frequencies used in medicine. For short (10 minutes or less) continuous wave exposure, with the exception of behavioral effects where variable results have been observed, this tabulation did not identify any in vivo or in vitro effects at spatial peak, temporal average (SPTA) intensities less than 100 mW/cm2. However, a number of effects using pulsed sources with SPTA intensities under this level have been reported. There are several frequently recurring topics in recent reports which include developmental effects and microstructure changes at the cellular level. In addition to animal investigations, there are some limited human epidemiological studies reporting an association between medical ultrasound exposure in utero and developmental effects. Although sufficient research has not been completed to draw conclusions, the findings deserve further investigation. A systematic pattern of directed research on a large scale is not apparent. The available data consist of many scattered studies conducted by individual investigators and groups throughout the world.

The precise nature and significance of SCEs are still not understood. It is clear that SCE analysis is a sensitive means of detecting genotoxic agents, and that SCEs are correlated with mutation, in vitro transformation, and cancer. SCEs, as all other short-term assays, are subject to false positives and false negatives. Therefore, it is possible that even if ultrasound induces SCE, the effects may not be deleterious, although the reverse could be true as well. The majority of studies have not observed SCE induction after exposure to diagnostic ultrasound, however two positive responses have been reported. Such discrepancies cannot be explained until investigators adopt a uniform protocol for ultrasound exposure. The currently widespread use of ultrasound in antepartum diagnosis, and the rate at which its use increases, argue strongly for additional research into its potential for genetic toxicity.

During the last three decades, medical ultrasound has grown from a new imaging tool used by only a few clinical pioneers to a diagnostic science now used worldwide in several clinical specialities. In one medical speciality alone, obstetrics, estimates of the percentage of pregnant women in the United States examined by diagnostic ultrasound range from 15–40% (NIH, 1984); in some countries, diagnostic ultrasound is a recommended routine prenatal procedure (NIH, 1984). The rapid development and expansion in the use of diagnostic ultrasound has been largely due to the perceived safety and medical benefits of this technology .

The action of ultrasound on morphological and functional states of identified central neurons — Mauthner cells (M-cells) — was investigated. M-cells are the pair of giant neurons in the fish medulla oblongata. They receive the numerous synaptic endings from vestibular apparatus, through acoustic nerve branches(1). M-cells innervate contralateral spinal motoneurones, which in turn govern the tail and body muscles. M-cells play a definite role in the modulation of fishes’ swimming activity, being intercalating neurons in the otolyths-musculature pathway. The latter point of view has been confirmed by numerous experimental data (2,3).

It has been suggested that fetal weight reduction by ultrasound exposure is linearly related to the dose parameter I 2 : t , where bdI is the intensity and bdt the exposure time. A direct test of the concept was conducted using CF-1 mice. No effect on fetal weight was found at values of the dose parameter large enough to produce measurable heating in the fetal and maternal tissues.

The diverse and ever-expanding application of ultrasound in medicine, dentistry, the laboratory, industry, commercial premises and even the home means that the majority of the population is exposed to ultrasound at some time in their life (frequently without realizing that they are being exposed). It is often argued that the majority of these ultrasound exposures are not associated with any known risk. However, in many instances this complacency may be based upon the fact that we have not yet examined the most sensitive end-points, or that we have been unable to detect a relatively small change in a population having a large inherent variability, or even that suitable investigative trials have simply not been performed. It is therefore desirable that people should be aware of when they are being exposed to ultrasound and the potential hazards which could result from that particular exposure. Where it is known (or strongly suspected) that the ultrasound exposure is hazardous, then relatively simple precautionary measures can usually be taken to minimize or eliminate these adverse effects. In the case of the industrial and laboratory applications of ultrasound (where some of the most serious potential hazards are to be found) it should be the responsibility of the employer, as well as the employee, to ensure that adequate safety measures are carried out. However, other exposure systems, such as the use of low-frequency airborne ultrasound as rodent repellers or burglar alarms in shops, art galleries and other buildings open to the general public, are more insidious. Here, the adverse effects may be psychological, more difficult to demonstrate, and also affect only a small proportion of the population. In this case public pressure may have to be brought to bear on both the manufacturers and users of these devices to ensure that the general public is not unnecessarily exposed to what could be an unpleasant or even a distressing level of ultrasound exposure.

The embryotoxicity of ultrasound exposure during pregnancy was investigated in DUB:(ICR) mice. On day 0 of gestation (day of plug), pregnant mice were assigned to one of five groups: cage control, sham exposed (0 W/cm2), 0.05 W/cm2, 0.50 W/cm2. or 1.00 W/cm2. Females were anesthetized on day 8 of gestation and their abdomens were shaved to assure good acoustic coupling. The animals were strapped on a lucite board and placed vertically into a distilled degassed water bath (30 degrees C) so that the abdomen was fully submerged and centered in the axis of the ultrasonic beam. Insonation was carried out using a PZT transducer with a radius of 1.27 cm and a frequency of 1 MHz under continuous wave conditions. Each animal was placed at a distance of 25 cm from the transducer and exposed to the appropriate intensity for 120 seconds. On day 17 of gestation, the maternal animals were killed, the uterine contents were examined, and live fetuses were weighed and then shipped in cold lactated Ringer's solution from Maryland to Arkansas. Fetuses were examined on the day following maternal sacrifice for external and visceral defects and skeletons were prepared and examined subsequently. Slight but significant differences were detected between the cage control and sham-exposed groups. No statistically significant changes were seen that could be attributed to ultrasound exposure, although there was a slight increase in the incidence of malformed fetuses and the occurrence of multiple malformations in individual fetuses as intensity of the ultrasonic exposure increased.

A review and analysis of studies of the effects of ultrasound exposure on human fetuses leads to a conclusion that there is no association of exposure with birthweight, hearing loss, or major congenital anomalies. Conflicting data from studies on birthweight is probably due to methodologic problems with the studies that have found positive associations. There have been few sound studies of the effects of in utero ultrasound exposure in humans. Limited studies to date are mostly reassuring, but it is premature to say that ultrasound has been proven safe for the human fetus. Further research on the question of biological effects of ultrasound in humans is needed, particularly the question of a possible association of ultrasound with dyslexia.

Ultrasound-induced bubble activity (cavitation) has been recently shown to actively transport and improve the distribution of therapeutic agents in tumors. However, existing cavitation-promoting agents are micron-sized and cannot sustain cavitation activity over prolonged time periods because they are rapidly destroyed upon ultrasound exposure. A novel ultrasound-responsive single-cavity polymeric nanoparticle (nanocup) capable of trapping and stabilizing gas against dissolution in the bloodstream is reported. Upon ultrasound exposure at frequencies and intensities achievable with existing diagnostic and therapeutic systems, nanocups initiate and sustain readily detectable cavitation activity for at least four times longer than existing microbubble constructs in an in vivo tumor model. As a proof-of-concept of their ability to enhance the delivery of unmodified therapeutics, intravenously injected nanocups are also found to improve the distribution of a freely circulating IgG mouse antibody when the tumor is exposed to ultrasound. Quantification of the delivery distance and concentration of both the nanocups and coadministered model therapeutic in an in vitro flow phantom shows that the ultrasound-propelled nanocups travel further than the model therapeutic, which is itself delivered to hundreds of microns from the vessel wall. Thus nanocups offer considerable potential for enhanced drug delivery and treatment monitoring in oncological and other biomedical applications.

Ultrasound can produce a variety of nonthermal bioeffects via acoustic cavitation. Most studies on cavitation effects pointed on the difficulty of initiating and controlling the cavitation phenomenon. Our objective is to obtain reproducible viability and transfection rate in the case of the application of a continuous low intensity ultrasound exposure. We propose to initiate and maintain cavitation in the medium by combining a continuous ultrasound exposure with periodical high amplitude bursts. Cells were exposed to ultrasound (444.5 kHz) transmitted through the bottom of twelve‐well culture plates containing prostatic cells (AT2, 2.5 106 cells/mL), the plasmid DsRed in transfection case (200 μg/mL) and culture media. The cavitation effects were evaluated on the cell viability and transfection, determined 0 to 3 days after exposure by a flow cytometer (FACScan; total counted events: 10 000). Bursts of 1.73 W/cm2 intensity level had no effect on cells when their duration was lower than 100 ms and their frequency lower than 4 bursts/min. When combined with continuous exposure, only one burst of 1.73 W/cm2 intensity level and 50 ms duration was sufficient to activate the cavitation phenomenon in the medium.

Localized delivery of drugs into an osteoarthritic cartilaginous lesion does not yet exist, which limits pharmaceutical management of osteoarthritis (OA). High-intensity focused ultrasound (HIFU) provides a means to actuate matter from a distance in a non-destructive way. In this study, we aimed to deliver methylene blue locally into bovine articular cartilage in vitro. HIFU-treated samples (n = 10) were immersed in a methylene blue (MB) solution during sonication (f = 2.16 MHz, peak-positive-pressure = 3.5 MPa, mechanical index = 1.8, pulse repetition frequency = 3.0 kHz, cycles per burst: 50, duty cycle: 7%). Adjacent control 1 tissue (n = 10) was first pre-treated with HIFU followed by immersion into MB; adjacent control 2 tissue (n = 10) was immersed in MB without ultrasound exposure. The MB content was higher (p p > 0.05). To conclude, HIFU delivers molecules into articular cartilage without major short-term concerns about safety. The method is a candidate for a future approach for managing OA.

The effects of low frequency ultrasound on exudate yield, breaking strength, cooking yield, water-holding capacity, color, and muscle microstructure were investigated by exposing pieces of lean muscle to slow tumbling and low frequency ultrasonic waves. Results indicated that beef rolls exposed to low frequency ultrasound without added salt were superior in breaking strength and cooking yield to those tumbled with neither ultrasound nor salt and were comparable in breaking strength, cooking yield, exudate yield and water-holding capacity to those tumbled with salt and no ultrasound exposure. Furthermore, the beef rolls exposed to ultrasound and no salt were superior in color to those to which salt was added. Low frequency ultrasound caused muscle fiber disruption and separation of up to approximately 1 cm in depth in muscle micro-structure in the pieces of lean muscle.

This paper described the need for adequate quantification of dosage by identifying the most relevant physical factors so that a proper risk assessment can be made for any treatments involving exposure to ultrasound. As a demonstration an acoustic quantity was plotted for a continuous ultrasound field and called Q representing the square of the pressure amplitude. It was shown that this quantity Q would be relevant to biological effects of ultrasound in several ways, such as in the derivation of radiation pressure which has relevance to insonation of cell cultures. Q is also applicable to temperature calculations and to cavitation which would occur most vigorously when the pressure amplitude is greatest. It was pointed out that the suitability of parameters chosen to quantify ultrasound exposure will depend on both the feasibility of measuring it, and its relevance to biological effects and safety.