~ O ~ P R ~ H E N S I EVALUATION VE OF A THOROTRAST PATIENT: AN OVERVIEW Lois B. Travis,',' Ronald L. Kathren,' Desirke Mays,*and Charles MJ, Mays§ ucts within the body. This knowledge is essential not only for determining risk coefficients to various tissues from Thorotrast but has the potential for more general applicability to determination of risk coeficients from other internal alpha-emitting radionuclides. In particular, despite their value for determination of biokinetics, dosimetry, and risk data, there have been few actual measurements of thorium and its progeny in the tissues of Thorotrast patients (Goldin et al. 1972). Also, to our knowledge, there has been no comprehensive wholebody evaluation similar to those done for certain radiation accident victims (Roessler and Magura 1985).
Abstract-For several decades, thousands of people received Thorotrast during the course of angiography and other radiologic procedures. Eventually, as the hazards of this radioactive, radiographic contrast agent became apparent, research was initiated to further evaluate its associated adverse effects. In 1988 and 1989, Charles W. Mays, together with colleagues at a variety of sites, developed a detailed protocol for the comprehensivepostmortem evaluation of one subject who had been administered Thorotrast 36 y previously. This case represents the Erst holistic approach to the analysis of Thorotrast in a whole body, simultaneously assembling clinical and autopsy ~ndings with dosimetric, radi~hemical, autoradiographic, and molecular evaluations. Health Phys. 4 3 ( 1 ) : 1 ~ - 11992 ~ Key words: Thorotrast; human organs; radiation, medical; radiation effects
WHOLE-BODY DONAT~ON In the concluding panel discussion at an international workshop on the risks from radium and Thorotrast held at the National Cancer Institute (NCI) in 1988, the late Charles W. Mays briefly described the postmortem radioanalysis program of whole-body donations to the U.S. Transuranium Registry (USTR) and suggested that a Thorotrast patient might make such a donation in order to ". . . enjoy the privilege to contribute to scientific knowledge past the time of his or her life" (Taylor et al. 1989). After this eloquent plea, a person who had been given Thorotrast some 36 y previously approached Mays and prearrangements were made for her body, upon death, to be donated for dosimetric, radiochemical, autoradiographic, and molecular studies. The autopsy case was unique in that the subject, a physician herself, was highly aware of her exposure and was intensely dedicated to making what might well be termed an ultimate gift through donation of her body for scientific purposes. Her exposure to Thorotrast occurred in 1953 when she underwent cerebral angiography for the evaluation of severe headaches following an automobile accident. Thorotrast was the radiographic contrast medium employed, and it is estimated that the subject received an injection of 25 mL, containing an unknown amount of thorium, a portion of which accidentally infiltrated the soft tissues adjacent to the right carotid artery when she fainted during the procedure. Other than this immediate complication, she suffered no apparent ill effects until the last decade of her life when she combatted multiple infections, developed a hematologic disorder, and displayed other signs
INTRODUCTION
FROM ABOUT 1930 to 1955, thousands of persons worldwide were administered colloidal thorium dioxide (Thorotrast)-a radioactive, radiographic contrast agent for angiography and other purposes. As the possible hazards of this insoluble and highly retained material became apparent, a fraction of the exposed population became the subject of intensive follow-up and study. Numerous conferences and workshops have recorded the results of these efforts. The history of the use of Thorotrast and subsequent epidemiologic studies of Thorotrast-exposed populations have been recently summarized by Stannard (1 988) and Muth (1989). Despite investigation over the years, there is still much that remains to be discovered regarding the hazards of Thorotrast and the biokinetics, dist~bution,and fate of colloidal thorium and its radioactive decay prod-
* Epidemiology and Biostatistics Program, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, MD 20852; Reprint requests to: Lois B. Travis, Epidemiology and Biostatistics Program, EPN 408, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, 6130 Executive Blvd., Rockville, MD 20852; U.S. Transuranium and Uranium Registries, Health Research and Education Center, Washington State University, 100 Sprout Road, Richland, WA 99352; Deceased. Radiation Epidemiology Branch, National Cancer Institute, EPN-408, Rockville, MD 20852. 00 1 7-9078/92/$3.00/0 Copyright 0 1992 Health Physics Society
*
10
Eyaluation of a Thorotrast patientOL. B. TRAVIS ET
and symptoms that may have been related to the deposition of Thorotrast. She died in June 1989, having voluntarily agreed to postmortem donation of her body to the U.S. Uranium Registry (USUR) and the NCI.
Table 1. Members of the 232Thdecay series. Nuclide
~MMEDIATEPOSTMORTEM EVALUATION During the relatively short time that followed the identification and recruitment of USUR Case 1001, Mays played a leading role in the development of plans for the postmortem evaluation of the tissues from this case. In conjunction with colleagues at several sites, he developed a detailed protocol specifying the temporal sequence of events to be initiated immediately upon the donor's death. This included provision for direct postmortem counting of specific tissues and organs as soon after death as practicable. This tactic was necessary in order to capture important information regarding the distribution and radioactive equilibrium states of 232Thand its long-lived decay products, specifically 228Raand 228Th,in the various tissues at the time of death, thereby gaining insight into the biokinetics and dosimetry of these nuclides during life. Direct postmortem counting of specific tissues and organs represented a significant departure from the normal procedures of the Registry, and required considerable preplanning and organization to mobilize personnel and technical capabilities immediately after the donor's death. The extensive coordination of the autopsy and subsequent direct counting of tissues was one of Mays' last projects. 232This the predominant naturally occumng isotope of thorium and the parent of the thorium series shown in Table 1 . The concentration and distribution
TvDe of radiation
232Th
Half-life
Alpha
1.4 X 10"
Beta
5.7
Beta, gamma
6.1 h
Alpha
1.9
Alpha
3.6 d
'"Rn
Alpha
55.6 s
U 2'6Po
Alpha
U ='Ra U "'Ac U '*'Th 2 2U4 h
TISSUE REGISTRIE~ The USTR and USUR are parallel tissue study programs that are concerned with the biokinetics, distribution, dosimetry, and radiological protection aspects of the actinide elements in humans (Kathren 1989). The USTR was organized in 1968 as the National Plutonium Registry to serve as a postmortem tissue study program of plutonium in OccupationaIly exposed persons. In 1970, to reflect the broader concern with the entire spectrum of transuranium elements, including americium and neptunium, the Registry was renamed the U.S. Transuranium Registry. The USUR was organized in 1978 to study uranium and its decay products in humans. Mays had served as a member of the Advisory Committee to the Registries for more than a decade and was well acquainted with both the practicality and potentially important scientific value of postmortem radiochemical analyses of tissue. Because 230This an important decay product of 238Uand because the biokinetic behavior of 230This not well-known, and because of the general applicability of the alpha dosimetry from this case, it was deemed appropriate to incorporate this Thorotrast case into the USUR. The case was officially designated as USUR Case 1001.
11
AL.
11
1
'I2Pb 'I
4. Bi
(64%)
(36%)
11
$1TI
2i2p0
U
2osPb
0.15 s
Beta, gamma
10.6 h
Beta, alpha
60.5 min
2'2Fo:Alpha 20ST1:Beta, gamma
0.3 PS 3 min Stable
of the different members of the decay chain in body tissues is determined by the complex inte~ctionof radioactive decay kinetics and the unique biokinetic behavior of each individual element, As seen in Table 1, some members of the decay chain have short radiological half-lives that would not be detected if significant delays in analysis occurred. Thus, counting of specific tissues and organs as soon as feasible after death was also an attempt to measure the activity from short-lived members of the decay chain, such as "'Bi which has a half-life of approximately 1 h. In particular, determination of the activity relationships of the various members of the thorium series was vital to the establishment of dosimetric information for sites where excess cancers have been observed or suggested in Thorotrast patients (van Kaick et al. 1989). COMPREHENSIVE POSTMORTEM EVALUATION The immediate postmortem counting was an integral part of a larger program of evaluation of tissue dist~bution,biokinetics, and dosimetry of thorium and its important long-lived progeny. This was accomplished by radiochemical analysis of the soft tissues and one-half the skeleton in accordance with the pre-established practice of the Registries (Kathren 1989). From these evaluations, risk coefficients for Thorotrast in various tissues could be developed and an attempt could be made to translate these risk c o e ~ ~ e nto t s other alpha-emitting radionuclides, notably 239Puand 241Am. Another important aspect of the overall program was the sharing of tissue samples with other scientists for numerous special studies, including bone and softtissue autoradiography and oncogene studies, thus pro-
12
Health Physics
viding additional dimensions to the overall research results.
DISCUSSION USUR Case 1001 represents the first holistic approach to the analysis of Thorotrast in a whole body, simultaneously assembling clinical and autopsy findings along with dosimetric, radiochemical, autoradiographic, and molecular ev~uations.The comprehensive evaluation of persons and populations exposed to Thorotrast is critically important, not only for what might be revealed about Thorotrast but also because of the greater potential for applicability to other populations exposed to internal alpha-emitting radionuclides. Since the opportunity to study such populations is limited, it is important to maximize the knowledge obtained from studies of exposed populations and individuals. The NCI is currently collaboratingwith the Danish Thorotrast study and anticipates a reactivation of previous studies in several other countriesas well. We hope that the detailed clinical, biokinetic, and dosimetric evaluations discussed in this special issue of Health Physics will help provide insights on how to better evaluate these exposed populations, and in such a way as to gain improved understanding of the mechanisms of carcinogenesisand to provide more precise estimates on the risks from i n t e ~ ~ deposited ly ~pha-emitting radionuclides. Among the important practical applications will be the establishment of firm scientifically based foundations to better guide health physicists and radiation biologists in the development of appropriate radiation protection standards. Included along with the published version of the papers is the complete discussion that followed their initial presentation at an informal collaborators' workshop jointly hosted by NCI and the USUR in the summer of 1990. The discussion from this meeting was fruitful in ideas and in future goals including the: (1) sharing of ongoing research efforts, both nationally and internationally; (2) consideration of whether radiochemical analysis of further whole-body donations should be pursued; (3) identification of additional research areas; and (4) issue of pot en ti^ studies in longterm survivors of Thorotrast, such as measurement of 220Rn'in expired air and various biochemical analyses of blood.
July 1992, Volume 63, Number 1
CONCLUSION We are indebted to USUR Case 1001 who, by the selfless bequeathal of her body, made this comprehensive study possible. We hope this collection of scientific papers will serve as a suitable memorial to her final gift to science and to our improved understanding of Thorotrast and other alpha-emitting substances in humans. We also hope that it will serve as a fitting memorial to our friend and colleague, Charles W. Mays, who devoted much of his extraordinary and highly productive career to the study of Thorotrast. ~ c ~ ~ o ~ ~ e ~ g eare ~ indebted e ~ f ~ to- John W e D. Boice, Jr. for critical review of the manuscript and to Ms. Maria Klebanoff for expert secretarial assistance. This work was supported in part by U.S. Department of Energy Contract DE-AC06-76-RLO 1837. The Hanford E n v i r o n m e n ~Health Foundation had contractual responsibility for administration of the US. Transuranium and Uranium Registries under the provisions of this contract until February 1992.
REFERENCES Goldin, A. S.; Magno, P. J.; Geiger, F.; Janower, M. L. Radionuclides in autopsy samples from Thorotrast patients. Health Phys. 22:471-482; 1972. Kathren, R. L. The United States Transuranium and Uranium Registries: Overview and recent progress. Radiat. Protect. Dosim. 26:323-330; 1989. Muth, H. History of the German Thorotrast studies. In: Risks from radium and Thorotrast, proceedings of a workshop held under the joint sponsorship of the U.S. Department of Energy, the U.S. National Cancer Institute, and the Radiation Protection Programme of the Commission of the European Communities. London: British Institute of Radiology; BIR Report 21; 1989: 93-97. RoessIer, G. S,; Magura, B., eds. The U.S. Transuranium Registry report on the 241Amcontent of a whole body. Health Phys. 49(4):559-661; 1985. Stannard, J. N. Radioactivity and health: A history. Washington, DC: Offce of Scientific and Technical information; DE-AC06-76RLO 1830; 1988: 247-257. Taylor, D. M.; Mays, C. W.; Gerber, G. B.; Thomas, R. G., eds. Risks &om radium and Thorotrast. London: British Institute of Radiology; BIR Report 2 1; 1989: 176- 179. van Kaick, G.; Wesch, H.; Luhrs, H.; Leibermann, D.; Kaui, A.; Muth, A. The German Thorotrast study-report on 20 years follow-up. In: Risks from radium and Thorotrast, proceedings of a workshop held under the joint sponsorship of the U.S. Department of Energy, the U.S. National Cancer Institute, and the Radiation Protection Programme of the Commission of the European Communities. London: British Institute of Radiology; BIR Report 2 1; 1989: 98-104
.a
Abstract-For several decades, thousands of people received Thorotrast during the course of angiography and other radiologic procedures. Eventually, as the hazards of this radioactive, radiographic contrast agent became apparent, research was initiated to further evaluate its associated adverse effects. In 1988 and 1989, Charles W. Mays, together with colleagues at a variety of sites, developed a detailed protocol for the comprehensivepostmortem evaluation of one subject who had been administered Thorotrast 36 y previously. This case represents the Erst holistic approach to the analysis of Thorotrast in a whole body, simultaneously assembling clinical and autopsy ~ndings with dosimetric, radi~hemical, autoradiographic, and molecular evaluations. Health Phys. 4 3 ( 1 ) : 1 ~ - 11992 ~ Key words: Thorotrast; human organs; radiation, medical; radiation effects
WHOLE-BODY DONAT~ON In the concluding panel discussion at an international workshop on the risks from radium and Thorotrast held at the National Cancer Institute (NCI) in 1988, the late Charles W. Mays briefly described the postmortem radioanalysis program of whole-body donations to the U.S. Transuranium Registry (USTR) and suggested that a Thorotrast patient might make such a donation in order to ". . . enjoy the privilege to contribute to scientific knowledge past the time of his or her life" (Taylor et al. 1989). After this eloquent plea, a person who had been given Thorotrast some 36 y previously approached Mays and prearrangements were made for her body, upon death, to be donated for dosimetric, radiochemical, autoradiographic, and molecular studies. The autopsy case was unique in that the subject, a physician herself, was highly aware of her exposure and was intensely dedicated to making what might well be termed an ultimate gift through donation of her body for scientific purposes. Her exposure to Thorotrast occurred in 1953 when she underwent cerebral angiography for the evaluation of severe headaches following an automobile accident. Thorotrast was the radiographic contrast medium employed, and it is estimated that the subject received an injection of 25 mL, containing an unknown amount of thorium, a portion of which accidentally infiltrated the soft tissues adjacent to the right carotid artery when she fainted during the procedure. Other than this immediate complication, she suffered no apparent ill effects until the last decade of her life when she combatted multiple infections, developed a hematologic disorder, and displayed other signs
INTRODUCTION
FROM ABOUT 1930 to 1955, thousands of persons worldwide were administered colloidal thorium dioxide (Thorotrast)-a radioactive, radiographic contrast agent for angiography and other purposes. As the possible hazards of this insoluble and highly retained material became apparent, a fraction of the exposed population became the subject of intensive follow-up and study. Numerous conferences and workshops have recorded the results of these efforts. The history of the use of Thorotrast and subsequent epidemiologic studies of Thorotrast-exposed populations have been recently summarized by Stannard (1 988) and Muth (1989). Despite investigation over the years, there is still much that remains to be discovered regarding the hazards of Thorotrast and the biokinetics, dist~bution,and fate of colloidal thorium and its radioactive decay prod-
* Epidemiology and Biostatistics Program, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, MD 20852; Reprint requests to: Lois B. Travis, Epidemiology and Biostatistics Program, EPN 408, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, 6130 Executive Blvd., Rockville, MD 20852; U.S. Transuranium and Uranium Registries, Health Research and Education Center, Washington State University, 100 Sprout Road, Richland, WA 99352; Deceased. Radiation Epidemiology Branch, National Cancer Institute, EPN-408, Rockville, MD 20852. 00 1 7-9078/92/$3.00/0 Copyright 0 1992 Health Physics Society
*
10
Eyaluation of a Thorotrast patientOL. B. TRAVIS ET
and symptoms that may have been related to the deposition of Thorotrast. She died in June 1989, having voluntarily agreed to postmortem donation of her body to the U.S. Uranium Registry (USUR) and the NCI.
Table 1. Members of the 232Thdecay series. Nuclide
~MMEDIATEPOSTMORTEM EVALUATION During the relatively short time that followed the identification and recruitment of USUR Case 1001, Mays played a leading role in the development of plans for the postmortem evaluation of the tissues from this case. In conjunction with colleagues at several sites, he developed a detailed protocol specifying the temporal sequence of events to be initiated immediately upon the donor's death. This included provision for direct postmortem counting of specific tissues and organs as soon after death as practicable. This tactic was necessary in order to capture important information regarding the distribution and radioactive equilibrium states of 232Thand its long-lived decay products, specifically 228Raand 228Th,in the various tissues at the time of death, thereby gaining insight into the biokinetics and dosimetry of these nuclides during life. Direct postmortem counting of specific tissues and organs represented a significant departure from the normal procedures of the Registry, and required considerable preplanning and organization to mobilize personnel and technical capabilities immediately after the donor's death. The extensive coordination of the autopsy and subsequent direct counting of tissues was one of Mays' last projects. 232This the predominant naturally occumng isotope of thorium and the parent of the thorium series shown in Table 1 . The concentration and distribution
TvDe of radiation
232Th
Half-life
Alpha
1.4 X 10"
Beta
5.7
Beta, gamma
6.1 h
Alpha
1.9
Alpha
3.6 d
'"Rn
Alpha
55.6 s
U 2'6Po
Alpha
U ='Ra U "'Ac U '*'Th 2 2U4 h
TISSUE REGISTRIE~ The USTR and USUR are parallel tissue study programs that are concerned with the biokinetics, distribution, dosimetry, and radiological protection aspects of the actinide elements in humans (Kathren 1989). The USTR was organized in 1968 as the National Plutonium Registry to serve as a postmortem tissue study program of plutonium in OccupationaIly exposed persons. In 1970, to reflect the broader concern with the entire spectrum of transuranium elements, including americium and neptunium, the Registry was renamed the U.S. Transuranium Registry. The USUR was organized in 1978 to study uranium and its decay products in humans. Mays had served as a member of the Advisory Committee to the Registries for more than a decade and was well acquainted with both the practicality and potentially important scientific value of postmortem radiochemical analyses of tissue. Because 230This an important decay product of 238Uand because the biokinetic behavior of 230This not well-known, and because of the general applicability of the alpha dosimetry from this case, it was deemed appropriate to incorporate this Thorotrast case into the USUR. The case was officially designated as USUR Case 1001.
11
AL.
11
1
'I2Pb 'I
4. Bi
(64%)
(36%)
11
$1TI
2i2p0
U
2osPb
0.15 s
Beta, gamma
10.6 h
Beta, alpha
60.5 min
2'2Fo:Alpha 20ST1:Beta, gamma
0.3 PS 3 min Stable
of the different members of the decay chain in body tissues is determined by the complex inte~ctionof radioactive decay kinetics and the unique biokinetic behavior of each individual element, As seen in Table 1, some members of the decay chain have short radiological half-lives that would not be detected if significant delays in analysis occurred. Thus, counting of specific tissues and organs as soon as feasible after death was also an attempt to measure the activity from short-lived members of the decay chain, such as "'Bi which has a half-life of approximately 1 h. In particular, determination of the activity relationships of the various members of the thorium series was vital to the establishment of dosimetric information for sites where excess cancers have been observed or suggested in Thorotrast patients (van Kaick et al. 1989). COMPREHENSIVE POSTMORTEM EVALUATION The immediate postmortem counting was an integral part of a larger program of evaluation of tissue dist~bution,biokinetics, and dosimetry of thorium and its important long-lived progeny. This was accomplished by radiochemical analysis of the soft tissues and one-half the skeleton in accordance with the pre-established practice of the Registries (Kathren 1989). From these evaluations, risk coefficients for Thorotrast in various tissues could be developed and an attempt could be made to translate these risk c o e ~ ~ e nto t s other alpha-emitting radionuclides, notably 239Puand 241Am. Another important aspect of the overall program was the sharing of tissue samples with other scientists for numerous special studies, including bone and softtissue autoradiography and oncogene studies, thus pro-
12
Health Physics
viding additional dimensions to the overall research results.
DISCUSSION USUR Case 1001 represents the first holistic approach to the analysis of Thorotrast in a whole body, simultaneously assembling clinical and autopsy findings along with dosimetric, radiochemical, autoradiographic, and molecular ev~uations.The comprehensive evaluation of persons and populations exposed to Thorotrast is critically important, not only for what might be revealed about Thorotrast but also because of the greater potential for applicability to other populations exposed to internal alpha-emitting radionuclides. Since the opportunity to study such populations is limited, it is important to maximize the knowledge obtained from studies of exposed populations and individuals. The NCI is currently collaboratingwith the Danish Thorotrast study and anticipates a reactivation of previous studies in several other countriesas well. We hope that the detailed clinical, biokinetic, and dosimetric evaluations discussed in this special issue of Health Physics will help provide insights on how to better evaluate these exposed populations, and in such a way as to gain improved understanding of the mechanisms of carcinogenesisand to provide more precise estimates on the risks from i n t e ~ ~ deposited ly ~pha-emitting radionuclides. Among the important practical applications will be the establishment of firm scientifically based foundations to better guide health physicists and radiation biologists in the development of appropriate radiation protection standards. Included along with the published version of the papers is the complete discussion that followed their initial presentation at an informal collaborators' workshop jointly hosted by NCI and the USUR in the summer of 1990. The discussion from this meeting was fruitful in ideas and in future goals including the: (1) sharing of ongoing research efforts, both nationally and internationally; (2) consideration of whether radiochemical analysis of further whole-body donations should be pursued; (3) identification of additional research areas; and (4) issue of pot en ti^ studies in longterm survivors of Thorotrast, such as measurement of 220Rn'in expired air and various biochemical analyses of blood.
July 1992, Volume 63, Number 1
CONCLUSION We are indebted to USUR Case 1001 who, by the selfless bequeathal of her body, made this comprehensive study possible. We hope this collection of scientific papers will serve as a suitable memorial to her final gift to science and to our improved understanding of Thorotrast and other alpha-emitting substances in humans. We also hope that it will serve as a fitting memorial to our friend and colleague, Charles W. Mays, who devoted much of his extraordinary and highly productive career to the study of Thorotrast. ~ c ~ ~ o ~ ~ e ~ g eare ~ indebted e ~ f ~ to- John W e D. Boice, Jr. for critical review of the manuscript and to Ms. Maria Klebanoff for expert secretarial assistance. This work was supported in part by U.S. Department of Energy Contract DE-AC06-76-RLO 1837. The Hanford E n v i r o n m e n ~Health Foundation had contractual responsibility for administration of the US. Transuranium and Uranium Registries under the provisions of this contract until February 1992.
REFERENCES Goldin, A. S.; Magno, P. J.; Geiger, F.; Janower, M. L. Radionuclides in autopsy samples from Thorotrast patients. Health Phys. 22:471-482; 1972. Kathren, R. L. The United States Transuranium and Uranium Registries: Overview and recent progress. Radiat. Protect. Dosim. 26:323-330; 1989. Muth, H. History of the German Thorotrast studies. In: Risks from radium and Thorotrast, proceedings of a workshop held under the joint sponsorship of the U.S. Department of Energy, the U.S. National Cancer Institute, and the Radiation Protection Programme of the Commission of the European Communities. London: British Institute of Radiology; BIR Report 21; 1989: 93-97. RoessIer, G. S,; Magura, B., eds. The U.S. Transuranium Registry report on the 241Amcontent of a whole body. Health Phys. 49(4):559-661; 1985. Stannard, J. N. Radioactivity and health: A history. Washington, DC: Offce of Scientific and Technical information; DE-AC06-76RLO 1830; 1988: 247-257. Taylor, D. M.; Mays, C. W.; Gerber, G. B.; Thomas, R. G., eds. Risks &om radium and Thorotrast. London: British Institute of Radiology; BIR Report 2 1; 1989: 176- 179. van Kaick, G.; Wesch, H.; Luhrs, H.; Leibermann, D.; Kaui, A.; Muth, A. The German Thorotrast study-report on 20 years follow-up. In: Risks from radium and Thorotrast, proceedings of a workshop held under the joint sponsorship of the U.S. Department of Energy, the U.S. National Cancer Institute, and the Radiation Protection Programme of the Commission of the European Communities. London: British Institute of Radiology; BIR Report 2 1; 1989: 98-104
.a
