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Thermal Teratology
EUROPEAN JOURNAL
ELSEVIER
European
Journal
of Ultrasound
EFSUMB:
9 (1999) 281
283
Tutorial
Thermal Teratology European
Committee
for Medical
1. Introduction Hyperthermia is a proven teratogen in mammalian biological systems and is considered to be a teratogen in humans (Graham et al.. 1998; Chambers et al., 1998). Since heat generation is a known outcome of exposure to diagnostic ultrasound. the question of the importance of a thermal interaction with embryo-fetal development is relevant. This tutorial article summarises the experimental data of thermal effects on animal embryo-fetal development and discusses the problems arising when relating these findings to thermal effects of diagnostic ultrasound.
2. Experimental
data
A significant body of information on thermal exposures producing teratogenic effects in animals has accumulated recently. These experiments include animal studies with a pregnant mouse, Chinese hamster, rat, guinea pig, marmoset, monkey, sheep, pig and chicken. Hyperthermia was mostly achieved by prolonged exposure to hot air or by * Corresponding author. Professor Dr med. Hans-Dieter Rott. Institut fiir Humangenetik der Universitat ErlangenNiirnberg. Schwabachanlage IO, D-91054 Erlangen. Tel.: + + 49-9 13 l-209297. E-mciil trti&.v.c 49-9131-8522319; fax: [email protected] (H.-D. Rott). 0929-8266:99/S
- see front
PII: SOY29-X266(99)00046-4
matter
B? 1999 Elsevier
Science
Ireland
Ultrasound
Safety (ECMUS)*
hot water bath and sometimes by radio-frequency radiation or injection of pyrogens. Temperature elevations up to 43.5”C were achieved, which means for some species 5°C above normal core temperature. A complicating fact is the variety of normal body temperatures between mammalian species, e.g. 38.5”C in rats, 39°C in pigs, and 39.5”C in rabbits and sheep, and even 42.5”C in chickens. Exposure duration varied from two minutes to two days (NCRP, 1992; AIUM, 1993; WFUMB, 1992, 1998). Thermal teratogenesis is a threshold effect. For exposure durations up to 50 h, there have been no significant biological effects observed due to temperature elevation less than or equal to 1.5”C above normal core temperature. For temperature increases greater than 1.5”C thresholds for teratogenie effects are determined by a combination of the induced temperature elevation and its duration. For temperature increases of 4°C and 6°C above normal the corresponding limits for the exposure duration have been estimated as 16 min and I min, respectively. The lowest absolute temperature value at which teratogenic effects have repeatedly been reported in mammals is 41.5”C. The bulk of literature shows that adverse developmental effects require a temperature increase of at least 1.5”C (AIUM, 1993). Observed thermal teratogenic effects include a variety of different outcomes and malformations of various organs, such as abortion, neural tube Ltd. All rights
reserved.
defects, brain growth retardation, anophthalmia, cataracts, cleft lip and cleft palate, heart malformations, skeletal, spinal and vertebral defects, and tooth defects. The malformation patterns were more determined by the embryonic or fetal stage of development at the exposure time than by the type of induction of temperature elevation (NCRP, 1992). Epidemiological studies have shown significant associations between maternal febrile illness during pregnancy and congenital malformations (Germain et al.. 1985). Other references are given in Miller and Ziskin (1989), and in Edwards (1986). The cause for these associations might, however. be the viral or infectious agent rather than the accompanying fever, although evidence has been published which casts doubt on this as a single cause (Sever. 1982). Mammalian tissues have apparently different sensitivities to thermal damage. In general, embryos are more susceptible to damage than fetuses due to the high rate of cellular activity during organogenesis. The brain is the most susceptible organ. In guinea pigs moderate heat exposure induced isolated, non-deforming retardation of brain growth and reduced learning performance. Moreover, the brain remains susceptible to heat throughout the whole pregnancy (WFUMB, 1998) and into infancy.
3. Problems relating clinical safety
animal
experiments
to
There are uncertainties in the extrapolation of experimental thermal effects to human risks due to ultrasound induced heating. One of the greatest difficulties lies in determining the human equivalent exposure conditions. A fundamental issue is whether or not to adopt the notion that there is a fixed absolute temperature that is critical for normal biochemical processes and development of all mammalian biological systems. The alternative view is that catalysts for biochemical reactions and enzymes may have operating temperatures that are specific for each species with similar limited ranges of tolerance. The conservative approach would be to adopt the second position and to translate the lowest threshold values in terms of
elevated temperature above the respective basal level into the threshold for human safety. The experiments on thermal teratology were performed by whole body heat exposure of the pregnant animals. This experimental design implies embryonic or fetal whole body hyperthermia. In contrast, ultrasonic heating is local. The heated tissue volumes are small and any effects depend on the thermal sensitivity of the target tissue. Moreover, the maternal stress is likely to be less pronounced. Although the reaction of cells may be identical in whole body and local hyperthermia, respectively, the maternal thermoregulation might be different. In most animal experiments the exposure times refer to maternal heating, the fetal temperature not being measured. Recent studies with rats heated in an hot air incubator have time constants on the order of 13 min per 1°C elevation in core temperature. This is an extremely slow heating rate compared to that caused by ultrasound absorption where substantial temperature elevations can occur within seconds. The time needed for fetal thermal effects might, therefore, be shorter than that estimated from the duration of maternal heating. There is a relationship between the amount of ultrasound induced heating and the gestational age that correlates with bone development. Fetal bone structures become increasingly prone to heating with advancing mineralisation. Secondary heating of soft tissue neighbouring the bone has also to be taken into consideration, particularly brain adjacent to the skull. This concern is appropriate for the fetus during the later stages ot pregnancy, and also for the neonate. In embryonic stages of development any adverse physical insult can produce bioeffects that are easier to detect, since they are more likely to be severe. However, the likelihood of producing a significant temperature increase in soft embryonic tissue is lower than in the body tissue of the fetus. Within the haematopoetic system the bone marrow is the main site of blood formation in the third trimester of pregnancy. It is an actively proliferating tissue encased in the bone and, with increasing mineralisation, is at special risk for ultrasonic heating. Barnett et al. (1997) observed
abnormalities in the nuclei of neutrophils as well as transient reductions in the production of neutrophils and monocytes following prenatal exposures to diagnostic ultrasound.
4. Conclusions
and recommendations
Because of the uncertainties in relating experimental results of thermal teratology to possible thermal effects of diagnostic ultrasound on embryo -fetal development, no definite conclusions can be drawn. At present, thermal effects of diagnostic ultrasound to human fetuses are neither proven nor definitely excluded. This fact is sometimes referred to as a potrntid risk. This term, which has repeatedly been misinterpreted, states that there is no known real risk that could be quantified in numerical values. However, due to the insufficient scientific data base there remains the possibility of damage in worst case situations. There is consensus that a diagnostic exposure that produces a maximum in-situ temperature rise of no more than 1.5”C above normal physiological level (37°C) may be used clinically without reservations on thermal grounds, and that a diagnostic exposure that elevates embryonic and fetal in-situ temperature above 41°C (4°C above normal) for 5 min or more should be considered potentially hazardous (WFUMB, 1998). The embryonic period is known to be particularly sensitive to any external influences. With increasing mineralisation of the fetal bone as the fetus develops the possibility increases of heating fetal bone and adjacent soft tissue. At present, B-and M-mode imaging appear to present no thermal risks. However, exposures used in pulsed Doppler modes can be higher, and may have the potential to heat tissue by a few degrees. Until further scientific information is available, investigations using pulsed or colour Doppler ultrasound should be carried out with careful control of output levels and should prudently limit exposure of critical structures, especially bone. Any exposure information provided by the manufacturer, for example in the form of displayed safety
indices (EFSUMB, 1996) should be used to gain awareness of the highest output conditions being used. Where on-line display is not available, particular care should be taken to minimise exposure times (EFSUMB, 1998).
References AIUM (American Institute of Ultrasound in Medicine). Biocffects & Safety of Diagnostic Ultrasound. AIUM. Laurel. MD. 1993. Barnett SB. Rott HD, Ter Haar GR, Ziskin MC, Macda K. The sensitivity of biological tishuc to ultrasound. Ultrasound Med Biol 1997;23:805- I?. Chambers CD. Johnson KA, Dick LM, Felix RJ. Jones KL. Maternal fever and birth outcome: a prospective sludy. Teratology 1998:58:251 7. Edwards MJ. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance. Teratogenesis. Carcinogencsis and Mutagenesis 1986:6:563-m 82. EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology). Thermal and mechanical Indices. Eur J Ultrasound 1996:4:145 150. EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology). Clinical Safety Statement for LXagnostic Ultrasound 1998. Eur J Ultrasound 1998;8:676X (in press). Gcrmain MA. Webster WS. Edwards MJ. Hyperthermia as a teratogen: parameters determining hyperthcrmia-induced head defects in the rat. Teratology 1985;31:265-72. Graham JM. Edwards Matthew J, Edwards Marshall J. Teratogen update: Gestational effects of maternal hypcrthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology 1998;58:209 2 I. Miller MW. Ziskm MC. Biological consequences of hyperthermia. Ultrasound Med Biol 1989;15:707~~22. NRCP (National Council for Radiation Protection and Measurements). Exposure Criteria for diagnostic ultrasound: Part I. Criteria based on thermal mechanisms. NRCP. Bethesda. MD, 1992. Seber JL. Infection in pregnancy. Teratology 1982;25:227-37. WFUMB (World Federation for Ultrasound in Medicine and Biology). Symposium on Safety and Standardisation in Medical Ultrasound: Issues and Recommendations Regarding Thermal Mechanisms for Biological Effects 01 Ultrasound. In: Barnett SB, Kossoff G (editors). Ultrasound Med Biol 1992. Special Issue: 18~9. WFUMB (World Federation for Ultrasound in Medicine and Biology). WFUMB Symposium on Safety of Ultrasound in Medlcinc: Conclusions and Recommendations on Thermal and Non-Thermal Mechanisms for Biological Effects of Ultrasound. In: Barnett SB (editor). Ultrasound Med Biol IY98;24:Supplcment I.
ELSEVIER
European
Journal
of Ultrasound
EFSUMB:
9 (1999) 281
283
Tutorial
Thermal Teratology European
Committee
for Medical
1. Introduction Hyperthermia is a proven teratogen in mammalian biological systems and is considered to be a teratogen in humans (Graham et al.. 1998; Chambers et al., 1998). Since heat generation is a known outcome of exposure to diagnostic ultrasound. the question of the importance of a thermal interaction with embryo-fetal development is relevant. This tutorial article summarises the experimental data of thermal effects on animal embryo-fetal development and discusses the problems arising when relating these findings to thermal effects of diagnostic ultrasound.
2. Experimental
data
A significant body of information on thermal exposures producing teratogenic effects in animals has accumulated recently. These experiments include animal studies with a pregnant mouse, Chinese hamster, rat, guinea pig, marmoset, monkey, sheep, pig and chicken. Hyperthermia was mostly achieved by prolonged exposure to hot air or by * Corresponding author. Professor Dr med. Hans-Dieter Rott. Institut fiir Humangenetik der Universitat ErlangenNiirnberg. Schwabachanlage IO, D-91054 Erlangen. Tel.: + + 49-9 13 l-209297. E-mciil trti&.v.c 49-9131-8522319; fax: [email protected] (H.-D. Rott). 0929-8266:99/S
- see front
PII: SOY29-X266(99)00046-4
matter
B? 1999 Elsevier
Science
Ireland
Ultrasound
Safety (ECMUS)*
hot water bath and sometimes by radio-frequency radiation or injection of pyrogens. Temperature elevations up to 43.5”C were achieved, which means for some species 5°C above normal core temperature. A complicating fact is the variety of normal body temperatures between mammalian species, e.g. 38.5”C in rats, 39°C in pigs, and 39.5”C in rabbits and sheep, and even 42.5”C in chickens. Exposure duration varied from two minutes to two days (NCRP, 1992; AIUM, 1993; WFUMB, 1992, 1998). Thermal teratogenesis is a threshold effect. For exposure durations up to 50 h, there have been no significant biological effects observed due to temperature elevation less than or equal to 1.5”C above normal core temperature. For temperature increases greater than 1.5”C thresholds for teratogenie effects are determined by a combination of the induced temperature elevation and its duration. For temperature increases of 4°C and 6°C above normal the corresponding limits for the exposure duration have been estimated as 16 min and I min, respectively. The lowest absolute temperature value at which teratogenic effects have repeatedly been reported in mammals is 41.5”C. The bulk of literature shows that adverse developmental effects require a temperature increase of at least 1.5”C (AIUM, 1993). Observed thermal teratogenic effects include a variety of different outcomes and malformations of various organs, such as abortion, neural tube Ltd. All rights
reserved.
defects, brain growth retardation, anophthalmia, cataracts, cleft lip and cleft palate, heart malformations, skeletal, spinal and vertebral defects, and tooth defects. The malformation patterns were more determined by the embryonic or fetal stage of development at the exposure time than by the type of induction of temperature elevation (NCRP, 1992). Epidemiological studies have shown significant associations between maternal febrile illness during pregnancy and congenital malformations (Germain et al.. 1985). Other references are given in Miller and Ziskin (1989), and in Edwards (1986). The cause for these associations might, however. be the viral or infectious agent rather than the accompanying fever, although evidence has been published which casts doubt on this as a single cause (Sever. 1982). Mammalian tissues have apparently different sensitivities to thermal damage. In general, embryos are more susceptible to damage than fetuses due to the high rate of cellular activity during organogenesis. The brain is the most susceptible organ. In guinea pigs moderate heat exposure induced isolated, non-deforming retardation of brain growth and reduced learning performance. Moreover, the brain remains susceptible to heat throughout the whole pregnancy (WFUMB, 1998) and into infancy.
3. Problems relating clinical safety
animal
experiments
to
There are uncertainties in the extrapolation of experimental thermal effects to human risks due to ultrasound induced heating. One of the greatest difficulties lies in determining the human equivalent exposure conditions. A fundamental issue is whether or not to adopt the notion that there is a fixed absolute temperature that is critical for normal biochemical processes and development of all mammalian biological systems. The alternative view is that catalysts for biochemical reactions and enzymes may have operating temperatures that are specific for each species with similar limited ranges of tolerance. The conservative approach would be to adopt the second position and to translate the lowest threshold values in terms of
elevated temperature above the respective basal level into the threshold for human safety. The experiments on thermal teratology were performed by whole body heat exposure of the pregnant animals. This experimental design implies embryonic or fetal whole body hyperthermia. In contrast, ultrasonic heating is local. The heated tissue volumes are small and any effects depend on the thermal sensitivity of the target tissue. Moreover, the maternal stress is likely to be less pronounced. Although the reaction of cells may be identical in whole body and local hyperthermia, respectively, the maternal thermoregulation might be different. In most animal experiments the exposure times refer to maternal heating, the fetal temperature not being measured. Recent studies with rats heated in an hot air incubator have time constants on the order of 13 min per 1°C elevation in core temperature. This is an extremely slow heating rate compared to that caused by ultrasound absorption where substantial temperature elevations can occur within seconds. The time needed for fetal thermal effects might, therefore, be shorter than that estimated from the duration of maternal heating. There is a relationship between the amount of ultrasound induced heating and the gestational age that correlates with bone development. Fetal bone structures become increasingly prone to heating with advancing mineralisation. Secondary heating of soft tissue neighbouring the bone has also to be taken into consideration, particularly brain adjacent to the skull. This concern is appropriate for the fetus during the later stages ot pregnancy, and also for the neonate. In embryonic stages of development any adverse physical insult can produce bioeffects that are easier to detect, since they are more likely to be severe. However, the likelihood of producing a significant temperature increase in soft embryonic tissue is lower than in the body tissue of the fetus. Within the haematopoetic system the bone marrow is the main site of blood formation in the third trimester of pregnancy. It is an actively proliferating tissue encased in the bone and, with increasing mineralisation, is at special risk for ultrasonic heating. Barnett et al. (1997) observed
abnormalities in the nuclei of neutrophils as well as transient reductions in the production of neutrophils and monocytes following prenatal exposures to diagnostic ultrasound.
4. Conclusions
and recommendations
Because of the uncertainties in relating experimental results of thermal teratology to possible thermal effects of diagnostic ultrasound on embryo -fetal development, no definite conclusions can be drawn. At present, thermal effects of diagnostic ultrasound to human fetuses are neither proven nor definitely excluded. This fact is sometimes referred to as a potrntid risk. This term, which has repeatedly been misinterpreted, states that there is no known real risk that could be quantified in numerical values. However, due to the insufficient scientific data base there remains the possibility of damage in worst case situations. There is consensus that a diagnostic exposure that produces a maximum in-situ temperature rise of no more than 1.5”C above normal physiological level (37°C) may be used clinically without reservations on thermal grounds, and that a diagnostic exposure that elevates embryonic and fetal in-situ temperature above 41°C (4°C above normal) for 5 min or more should be considered potentially hazardous (WFUMB, 1998). The embryonic period is known to be particularly sensitive to any external influences. With increasing mineralisation of the fetal bone as the fetus develops the possibility increases of heating fetal bone and adjacent soft tissue. At present, B-and M-mode imaging appear to present no thermal risks. However, exposures used in pulsed Doppler modes can be higher, and may have the potential to heat tissue by a few degrees. Until further scientific information is available, investigations using pulsed or colour Doppler ultrasound should be carried out with careful control of output levels and should prudently limit exposure of critical structures, especially bone. Any exposure information provided by the manufacturer, for example in the form of displayed safety
indices (EFSUMB, 1996) should be used to gain awareness of the highest output conditions being used. Where on-line display is not available, particular care should be taken to minimise exposure times (EFSUMB, 1998).
References AIUM (American Institute of Ultrasound in Medicine). Biocffects & Safety of Diagnostic Ultrasound. AIUM. Laurel. MD. 1993. Barnett SB. Rott HD, Ter Haar GR, Ziskin MC, Macda K. The sensitivity of biological tishuc to ultrasound. Ultrasound Med Biol 1997;23:805- I?. Chambers CD. Johnson KA, Dick LM, Felix RJ. Jones KL. Maternal fever and birth outcome: a prospective sludy. Teratology 1998:58:251 7. Edwards MJ. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance. Teratogenesis. Carcinogencsis and Mutagenesis 1986:6:563-m 82. EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology). Thermal and mechanical Indices. Eur J Ultrasound 1996:4:145 150. EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology). Clinical Safety Statement for LXagnostic Ultrasound 1998. Eur J Ultrasound 1998;8:676X (in press). Gcrmain MA. Webster WS. Edwards MJ. Hyperthermia as a teratogen: parameters determining hyperthcrmia-induced head defects in the rat. Teratology 1985;31:265-72. Graham JM. Edwards Matthew J, Edwards Marshall J. Teratogen update: Gestational effects of maternal hypcrthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology 1998;58:209 2 I. Miller MW. Ziskm MC. Biological consequences of hyperthermia. Ultrasound Med Biol 1989;15:707~~22. NRCP (National Council for Radiation Protection and Measurements). Exposure Criteria for diagnostic ultrasound: Part I. Criteria based on thermal mechanisms. NRCP. Bethesda. MD, 1992. Seber JL. Infection in pregnancy. Teratology 1982;25:227-37. WFUMB (World Federation for Ultrasound in Medicine and Biology). Symposium on Safety and Standardisation in Medical Ultrasound: Issues and Recommendations Regarding Thermal Mechanisms for Biological Effects 01 Ultrasound. In: Barnett SB, Kossoff G (editors). Ultrasound Med Biol 1992. Special Issue: 18~9. WFUMB (World Federation for Ultrasound in Medicine and Biology). WFUMB Symposium on Safety of Ultrasound in Medlcinc: Conclusions and Recommendations on Thermal and Non-Thermal Mechanisms for Biological Effects of Ultrasound. In: Barnett SB (editor). Ultrasound Med Biol IY98;24:Supplcment I.