PUBLIC HEALTH BRIEFS
Rabies Vaccine Adsorbed: Neutralizing Antibody Titers after Three-Dose Pre-exposure Vaccination BYRON S. BERLIN, MD Abstract: Field trials at several schools of veterinary medicine showed that three-dose pre-exposure rabies vaccination with Rabies Vaccine Adsorbed developed by the Michigan Department of Health elicited neutralization antibody in practically all recipients two to three weeks after immunization. Titers declined during the first six months after vaccination. However, by 18 to 24 months, 98 percent of recipients still had titers equal or greater than a 1:5 dilution of serum. (Am J Public Health 1990; 80:476-478.)
Introduction Initial clinical trials with Rabies Vaccine Adsorbed (RVA), a new tissue culture derived rabies vaccine developed by the Michigan Department of Public Health,' were done with a two-dose pre-exposure immunization schedule.2 The studies showed that this new vaccine induced satisfactory antibody titers two to three weeks after vaccination and prepared recipients for a vigorous response to booster vaccination. Additional clinical trials, summarized in the present study, were conducted to ascertain antibody responses after administration of this vaccine by pre-exposure immunization schedules recommended by the Immunization Practices Advisory Committee (ACIP), Centers for Disease Control, i.e., three doses ofrabies vaccine oftissue culture origin, one dose each day on days 0, 7, and 21 or 28 days.3
Methods Vaccine
The vaccine used in the present study was previously
described.' Briefly, RVA contains non-infectious, B-propiolactone-treated rabies virus which is adsorbed onto aluminum phosphate. The virus was grown on diploid fetal rhesus monkey lung fibroblasts (FRh1-2), the rhesus analogue of the WI-38 cell. The antigenic potency of each lot of RVA exceeds 2.5 International Units (IU). Subjects The study consisted of 24 separate clinical subtrials with a combined enrollment of 1,735 students and staffs from five schools of veterinary medicine: 1,647 with no prior vaccination against rabies and 88 who had not responded to Duck Embryo Rabies Vaccine. The number of volunteers in individual subtrials varied from 16 to 127 and the median size was between 68 and 74 persons. Each person received three intramuscular injections of RVA, 1.0 mL per dose, at 0, 7, and 21 or 28 days and then was bled two weeks after the final dose of vaccine and, depending on the subtrial in which they were included, at six months and nine to 14 months. Volunteers remaining on the campuses were bled 18 to 24 months Address reprint requests to Byron S. Berlin, MD, Coordinating Physician, Bureau of Laboratory and Epidemiological Services, Michigan Department of Public Health, P.O. Box 30035, 3500 N. Logan Street, Lansing, MI 48909. This paper, submitted to the Journal March 6, 1989, was revised and accepted for publication September 20, 1989. © 1990 American Journal of Public Health 0090-0036/90$1.50
476
after vaccination (Table 1). Serum samples were sent to the Michigan Department of Public Health laboratories for antibody determination. Each volunteer provided a brief medical history and signed an informed consent before vaccination. Serology
Serum neutralization titers were ascertained by the Rapid Fluorescent Focus Inhibition Test (RFFIT)4 beginning with a 1:5 dilution of the serum and ending with a 1:625 dilution using five-fold dilutions. RFFIT titers, given as International Units (IU), were computed by dividing the reciprocal of the dilution titer of the subject's serum by the reciprocal of the dilution titer of a standard serum, designated as 1.0 IU, tested at the same time. RFFIT titers less than 1:5 dilution of serum, approximately 0.1 IU were considered below the minimally acceptable titer recommended by the ACIP.3 Titers from 0.2 to 0.5 IU were classed as acceptable because they fell between 0.1 IU and the minimally acceptable initial RFFIT response to post-exposure immunization recommended by the World Health Organization (0.5 IU).5 Titers above 25 IU were grouped together because the maximum dilution for testing the sera was 1:625.
Results Ninety-six percent (1,673/1,735) of the vaccinees were bled two weeks after the last dose of the vaccine series (Table 1). Nineteen (1 percent) had either withdrawn voluntarily or were dismissed from the study because of illness or reaction to the vaccine. Forty-three (2 percent) failed to return for bleeding. All but one of the 1,673 who were bled at two weeks had rabies neutralizing antibody titers greater than 0.1 IU. Subsequently, 91 percent (419/461) of volunteers initially enrolled in five of the 23 subtrials were bled six months after the vaccine series (Table 1) and, of these, 415 (99 percent) had RFFIT titers greater than 0.1 IU. Nine to 14 months after completing the vaccine series, blood samples were obtained from 761/984 (77 percent) volunteers enrolled in 13 subtrials. Of these, 748 (98%) also had RFFIT titers equal or greater than 0.1 IU. Finally, 308 persons (52 percent of the initial TABLE 1-Rabies Vaccine Study Plan Time and Number of Persons Bled Number of Subtrials
Number of Volunteers
Two Weeks
7 1 3 6 1 4 2
360 101 251 431 109 366 117 (1,735)
348 99 249 413 109 350 105 (1,673) 1
Total (24) Percent0.1 IU Number of initial volunteers Percent of initial volunteers bled
1,735 96
6 mos
9-14
18-24
mos
mos
84 234 N.D.* 101 N.D. N.D. (419) 4 461
179 301 N.D. 281 N.D. (761) 13 984
98 133 77 (308) 5 592
91
77
52
*Not Done.
AJPH April 1990, Vol. 80, No. 4
PUBLIC HEALTH BRIEFS TABLE 2-Persistence of RFFIT Titers after Pre-exposure Vaccination with Rhosus Diploid Rabies Vaccine RFFIT Titer Range***
Number Enrolled
Antigen content*
Schedule Days"
Median Titer***
Bleeding Time
25
Number
6.4 2.2 1.2 5.4 0.3 5.4 0.4
2 wks 6 mos 18 mos 2 wks 22 mos 2 wks 2 yrs
0 0 1 0 2 0 7
0 2 23 0 26 0 12
0 23 22 1 13 1 10
25 57 46 9 8 3 3
52 9 2 33 5 21 1
12 2 0 9 1 7 0
5 1 0 3 0 2 1
94 94 94 55 55 34 34
109
2.6
0-7-28
74
2.6
0-7-21
88
3.0(a)
0-7-28
*Antigenic Potency expressed as Intemational Units (IU). -Days of Injection. ***RFFIT Tter expressed as Intemational Units (IU). (a)Vaccine contained 1:10,000 thiomerosal as a preservative.
volunteers in seven subtrials) volunteered to be bled from 18 to 24 months after vaccination. Ninety-eight percent (303/ 308) still had titers equal to or greater than 0.1 IU. The findings in three representative clinical subtrials in which neutralizing antibody titers are presented only for persons from whom successive blood samples were obtained at each indicated time are shown in Table 2. Successive blood samples were obtained from 86 percent (94/109), 74 percent (55/74), and 39 percent (34/88) of volunteers initially enrolled in the respective trials. Two weeks after the third and final injection of RVA, median RFFIT titers in the three subtrials were 6.4, 5.4 and 5.4 IU, respectively. All recipients in these subtrials had neutralizing antibody at two weeks and, in those tested, at six months after vaccination. However, neutralizing antibody titers six months after vaccination were lower than those at two weeks. Eighteen months to two years post-vaccination, median RFFIT titers were from to 0.3 to 1.2 IU and 261/271 (96 percent) of the volunteers had titers equal to or greater than 0.1 IU. Discussion The findings summarized in the present study show that the seroconversion rate after pre-exposure vaccination with RVA, given by the currently recommended three dose schedules, approximated 100 percent. However, the duration of the antibody response after initial pre-exposure rabies immunization is as important a concern as the seroconversion rate in evaluating immune responses to rabies vaccines because neutralizing antibody, actively induced by vaccination or passively acquired, is a key factor in protection against rabies infection.69 Yet, determination of the duration of responses to vaccination in sizable populations is complicated by reason of attrition of volunteers. Attrition rates at six months and at nine to 14 months in this study were 9 percent and 23 percent, respectively; these rates probably have little effect on the interpretation of the results in view of the finding that 94 percent of recipients or more had titers equal to or greater than 0.1 IU. On the other hand, even though the attrition rate for those bled 18 months to two years after vaccination was 48 percent, the percent of volunteers showing neutralizing antibody at that time is considered a good approximation of persistence of antibody because titers at two weeks in those who were bled later did not appear different than those in persons who were not bled at the later time. Although RVA and human diploid cell culture vaccine (HDCV) have not been compared to each other in concurrent clinical trials, the seroconversion rate, persistence of rabies AJPH April 1990, Vol. 80, No. 4
neutralizing antibody, and adverse reactions after pre-exposure immunization with RVA appear practically the same as those obtained with HDCV.2"l'9 ACKNOWLEDGMENTS The author wishes to acknowledge the contributions of Dr. N. McCullough, Michigan State University, East Lansing, MI (deceased); Drs. L.J. Swango and D. Oleson, Auburn University, Auburn, AL; Dr. C. Smith and Mrs. Elaine Pratt, Ohio State University, Columbus OH; Dr. C. Goswick and Mrs. Mary Scott, Texas A&M University, College Station, TX, for contributions to this study.
REFERENCES 1. Burgoyne GH, Kajiya KD, Brown DW, Mitchell JR: Rhesus diploid rabies vaccine (adsorbed): A new rabies vaccine using FRhL-2 cells. J Infect Dis 1985; 152:204-210. 2. Berlin BS, Mitchell JR, Burgoyne GH, et al: A new rabies vaccine (Adsorbed): Results of initial clinical studies of preexposure vaccination. JAMA 1982; 247:1726-1728. 3. Immunization Practices Advisory Committee (ACIP): Rabies prevention-United States, 1984. MMWR 1984; 33:393-402. 4. Smith JS, Yager PA, Baer GM: A rapid reproducible test for determining rabies neutralizing antibody. Bull WHO 1973; 48:535-541. 5. WHO Expert Committee on Rabies, 7th Report. WHO Technical Report Series 709. Geneva: WHO, 1984. 6. Wiktor TJ: Dynamics of rabies infection. In: International Symposium on Rabies. Symp Series Immunobiol Standard 1966; 1:65-80. 7. Karliner JS, Belavel GS: Incidence of reactions following administration of antirabies serum. JAMA 1965; 193:359-362. 8. Celis E, Wiktor TJ, Dietzchold B, Koprowski H: Amplification of rabies virus induced stimulation of human T-cell lines and clones by antigenspecific antibodies. J Virol 1985; 56:426-433. 9. Turner GS: Immune response after rabies vaccination: Basic aspects. An Institut Pasteur/Virology 1985; 136E:453-460. 10. Wiktor TJ, Plotkin SA, Koprowski H: Development and clinical trials of the new human rabies vaccine of tissue culture (human diploid cell) Origin. Dev Biol Standard 1978; 40:3-9. 11. Plotkin SA, Wiktor TJ, Koprowski H, et al: Immunization schedules for the new human diploid rabies vaccine. J Epidemiol 1976; 103:75-80. 12. Turner GS, Nicholson KG, Tyrrell DAJ, et al: Evaluation of a human diploid cell strain rabies vaccine: Final report of a three year study of pre-exposure immunization. J Hyg (Cambridge) 1982; 89:101-110. 13. Ajjan N, Soulebot JP, Stellman C, et al: Resultats de la vaccination antirabique preventive par le vaccin inactive concentre souche rabies PM/WI-38-1503-3M cultivee sur cellules diploides humaines. Dev Biol Standard 1978; 40:89-100. 14. Kuwert EK, Marcus I, Hoher PG: Neutralizing and complement-fixing antibody responses in pre- and post-exposure vaccines to a rabies vaccine produced in human diploid cells. J Biol Standard 1976; 4:249-262. 15. Cox JH, Schneider LG: Prophylactic immunization of humans against rabies by intradermal inoculation of human diploid cell culture vaccine. J Clin Microbiol 1976; 3:96-101. 16. Roumaintzeff M, Ajjan N, Vincent-Falquet JC: Experience with preexposure rabies vaccination. Rev Infect Dis 1988; 10 (suppl 4):S751-S757. 17. Rosanoff E, Tint H: Responses to human diploid cell rabies vaccine: Neutralizing antibody responses of vaccine receiving booster doses of human diploid cell rabies vaccine. Am J Epidemiol 1979; 110:322-327.
477
PUBLIC HEALTH BRIEFS 18. Dressen DW, Kemp DT, Brown J, Brown WJ: Antibody response to a single intradermal booster dose of rabies human diploid cell vaccine. JAVMA 1983; 183:1468-1469.
19. Bernard KW, Mallonee J, Wright JC, et al: Preexposure immunization with intradermal human diploid cell rabies vaccine. JAMA 1987; 257:10561063.
Health Effects of a Thorium Waste Disposal Site G. REZA NAJEM, MD, PHD, Abstract: A case-control study of 112 households residing in the vicinity of a thorium waste disposal site found a higher prevalence of birth defects (RR 2.1) and liver diseases (RR 2.3) among exposed than the unexposed group. The numbers were quite small and the confidence intervals wide, however, so that no definite conclusions can be drawn from these data. (Am J Public Health 1990; 80:478480.)
Introduction Several studies have appeared in the medical literature analyzing possible adverse health effects for persons living in the vicinity of hazardous waste disposal sites.'-3 To our knowledge there is no published study in which the health effects of a thorium waste disposal site (TWDS) on the general population have been investigated, except for a community-based study in China.4 That study found no deleterious health effects from exposure to thorium, but had very low statistical power. The main concern about the possible biological effects of thorium (Th) with a half life of 1.4 x 1010 years is based on its radioactive characteristics and isotopes.5 Thorium232 is the parent of various radio-isotopes including 228Ra (radium), 228Ac (actinium), 228Th, 224Ra, and 220Rn (radon)5, Current interest is based in part on increased use of thorium as an energy source, e.g., in reactors using 232Th to produce 233U.6 Industrial and mining exposure to thorium have resulted in an increased incidence of lung cancer, pancreatic cancer, colorectal cancers, chronic respiratory diseases, liver damage, and other serious illnesses.7-9 Skeletal sarcomas, thorotrastomas, and sarcomas of the reticuloendo-thelial system have been reported from a study of patients receiving intravenous injections of thorotrast, a collodial solution of thorium oxide that was used as a contrast medium for diagnostic radiographic studies from the 1930s to the 1950s.'0 The purpose of this study was to conduct a survey of health effects of a thorium waste disposal site among members of the general population of Wayne, New Jersey, USA. Thorium Waste Disposal Site
The site is located on a 6.5 acre tract of land in Wayne Township, Passaic County in northern New Jersey, USA.* The population density in Wayne is 1,867.2 per square miles and annual per capita income is $7,725. "1 The thorium waste burial site lies within 100 feet of the sidewalk. Commercial Address reprint requests to G. Reza Najem, MD, PhD, Department of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School, 185 S. Orange Avenue, Newark, NJ 07103-2757. Ms. Voyce is with the New Jersey Institute of Technology, Newark. This paper, submitted to the Journal July 24, 1987, was revised and accepted for publication August 1, 1989. *New Jersey Department of Environmental Protection: Site Descriptions for Hazardous Waste Sites in New Jersey. Division of Waste Management, Hazardous Site Mitigation Administration, 1984/85. © 1990 American Journal of Public Health 0090-0036/90$1.50
478
AND
LISA K. VOYCE, MSENE
businesses, a nursing home, a school bus maintenance yard, and residential homes are adjacent to the site. A drainage ditch lies at the northern and eastern borders, and drains into a brook at the northeast corner of the burial field. The brook (a tributory to the Pompton River) flows through residential areas (copy of map available on request). Fresh water wetlands lie approximately 1,800 feet to the west of the thorium waste disposal site.* From 1948 until 1971, a company extracted thorium and rare earths from monazite ore, for usage by the Atomic Energy Commission.* During its active years, the plant waste was dumped in backyard sludge piles. The wastes have been buried only in the last few years, after spending over 20 years above the ground.** Surveys of the New Jersey Department of Environmental Protection showed readings of 40-1491 uR/hour (uR = micro-rad, micro being 10-6) in various regions classified as contaminated areas; Sheffield Brook contamination occurs within 10 meters of both sides. Soil samples revealed Thorium (232Th), Radium (238Ra) and Uranium (238Ur) in the contaminated regions. Water samples from Sheffield Brook and the drainage ditch showed mainly alpha and beta activity. Most of the air concentrations (ambient and indoor) were within the background radiation levels (approximately 150 mrem/year) The US Environmental Protection Agency (EPA) standard for home concentration is below 4 pCi/ liter.*** The residents of the households in the vicinity of the thorium waste disposal site and in the vicinity of contaminated Sheffield Brook have not been tested for radioactive materials uptake. Methods The exposed population included 76 households within three blocks adjoining the contaminated areas. The 76 comparison (unexposed) households included all houses located on about 9th and 10th blocks distance from the thorium waste disposal site and contaminated Sheffield Brook. Households were accepted for inclusion in the study if they had resided at the present address for at least five years. Eleven and 10 households of the exposed and unexposed groups, respectively, did not meet the criteria for eligibility, 10 and nine households, respectively, did not participate in the study due primarily to members not being at home at the time of scheduled interviews or having moved out without leaving forwarding addresses. Face-to-face interviews of all 112 households (362 members), using a structured questionnaire, were carried out by one interviewer who did not know exposure status; 32 household members who did not agree to a face-to-face **New Jersey Department of Environmental Protection. Unpublished data. ***US Environmental Protection Agency, Office of Radiation Programs, Washington, DC 20406. Further details on measurements of exposed areas are available on request to author (Najem). AJPH April 1990, Vol. 80, No. 4
Rabies Vaccine Adsorbed: Neutralizing Antibody Titers after Three-Dose Pre-exposure Vaccination BYRON S. BERLIN, MD Abstract: Field trials at several schools of veterinary medicine showed that three-dose pre-exposure rabies vaccination with Rabies Vaccine Adsorbed developed by the Michigan Department of Health elicited neutralization antibody in practically all recipients two to three weeks after immunization. Titers declined during the first six months after vaccination. However, by 18 to 24 months, 98 percent of recipients still had titers equal or greater than a 1:5 dilution of serum. (Am J Public Health 1990; 80:476-478.)
Introduction Initial clinical trials with Rabies Vaccine Adsorbed (RVA), a new tissue culture derived rabies vaccine developed by the Michigan Department of Public Health,' were done with a two-dose pre-exposure immunization schedule.2 The studies showed that this new vaccine induced satisfactory antibody titers two to three weeks after vaccination and prepared recipients for a vigorous response to booster vaccination. Additional clinical trials, summarized in the present study, were conducted to ascertain antibody responses after administration of this vaccine by pre-exposure immunization schedules recommended by the Immunization Practices Advisory Committee (ACIP), Centers for Disease Control, i.e., three doses ofrabies vaccine oftissue culture origin, one dose each day on days 0, 7, and 21 or 28 days.3
Methods Vaccine
The vaccine used in the present study was previously
described.' Briefly, RVA contains non-infectious, B-propiolactone-treated rabies virus which is adsorbed onto aluminum phosphate. The virus was grown on diploid fetal rhesus monkey lung fibroblasts (FRh1-2), the rhesus analogue of the WI-38 cell. The antigenic potency of each lot of RVA exceeds 2.5 International Units (IU). Subjects The study consisted of 24 separate clinical subtrials with a combined enrollment of 1,735 students and staffs from five schools of veterinary medicine: 1,647 with no prior vaccination against rabies and 88 who had not responded to Duck Embryo Rabies Vaccine. The number of volunteers in individual subtrials varied from 16 to 127 and the median size was between 68 and 74 persons. Each person received three intramuscular injections of RVA, 1.0 mL per dose, at 0, 7, and 21 or 28 days and then was bled two weeks after the final dose of vaccine and, depending on the subtrial in which they were included, at six months and nine to 14 months. Volunteers remaining on the campuses were bled 18 to 24 months Address reprint requests to Byron S. Berlin, MD, Coordinating Physician, Bureau of Laboratory and Epidemiological Services, Michigan Department of Public Health, P.O. Box 30035, 3500 N. Logan Street, Lansing, MI 48909. This paper, submitted to the Journal March 6, 1989, was revised and accepted for publication September 20, 1989. © 1990 American Journal of Public Health 0090-0036/90$1.50
476
after vaccination (Table 1). Serum samples were sent to the Michigan Department of Public Health laboratories for antibody determination. Each volunteer provided a brief medical history and signed an informed consent before vaccination. Serology
Serum neutralization titers were ascertained by the Rapid Fluorescent Focus Inhibition Test (RFFIT)4 beginning with a 1:5 dilution of the serum and ending with a 1:625 dilution using five-fold dilutions. RFFIT titers, given as International Units (IU), were computed by dividing the reciprocal of the dilution titer of the subject's serum by the reciprocal of the dilution titer of a standard serum, designated as 1.0 IU, tested at the same time. RFFIT titers less than 1:5 dilution of serum, approximately 0.1 IU were considered below the minimally acceptable titer recommended by the ACIP.3 Titers from 0.2 to 0.5 IU were classed as acceptable because they fell between 0.1 IU and the minimally acceptable initial RFFIT response to post-exposure immunization recommended by the World Health Organization (0.5 IU).5 Titers above 25 IU were grouped together because the maximum dilution for testing the sera was 1:625.
Results Ninety-six percent (1,673/1,735) of the vaccinees were bled two weeks after the last dose of the vaccine series (Table 1). Nineteen (1 percent) had either withdrawn voluntarily or were dismissed from the study because of illness or reaction to the vaccine. Forty-three (2 percent) failed to return for bleeding. All but one of the 1,673 who were bled at two weeks had rabies neutralizing antibody titers greater than 0.1 IU. Subsequently, 91 percent (419/461) of volunteers initially enrolled in five of the 23 subtrials were bled six months after the vaccine series (Table 1) and, of these, 415 (99 percent) had RFFIT titers greater than 0.1 IU. Nine to 14 months after completing the vaccine series, blood samples were obtained from 761/984 (77 percent) volunteers enrolled in 13 subtrials. Of these, 748 (98%) also had RFFIT titers equal or greater than 0.1 IU. Finally, 308 persons (52 percent of the initial TABLE 1-Rabies Vaccine Study Plan Time and Number of Persons Bled Number of Subtrials
Number of Volunteers
Two Weeks
7 1 3 6 1 4 2
360 101 251 431 109 366 117 (1,735)
348 99 249 413 109 350 105 (1,673) 1
Total (24) Percent0.1 IU Number of initial volunteers Percent of initial volunteers bled
1,735 96
6 mos
9-14
18-24
mos
mos
84 234 N.D.* 101 N.D. N.D. (419) 4 461
179 301 N.D. 281 N.D. (761) 13 984
98 133 77 (308) 5 592
91
77
52
*Not Done.
AJPH April 1990, Vol. 80, No. 4
PUBLIC HEALTH BRIEFS TABLE 2-Persistence of RFFIT Titers after Pre-exposure Vaccination with Rhosus Diploid Rabies Vaccine RFFIT Titer Range***
Number Enrolled
Antigen content*
Schedule Days"
Median Titer***
Bleeding Time
25
Number
6.4 2.2 1.2 5.4 0.3 5.4 0.4
2 wks 6 mos 18 mos 2 wks 22 mos 2 wks 2 yrs
0 0 1 0 2 0 7
0 2 23 0 26 0 12
0 23 22 1 13 1 10
25 57 46 9 8 3 3
52 9 2 33 5 21 1
12 2 0 9 1 7 0
5 1 0 3 0 2 1
94 94 94 55 55 34 34
109
2.6
0-7-28
74
2.6
0-7-21
88
3.0(a)
0-7-28
*Antigenic Potency expressed as Intemational Units (IU). -Days of Injection. ***RFFIT Tter expressed as Intemational Units (IU). (a)Vaccine contained 1:10,000 thiomerosal as a preservative.
volunteers in seven subtrials) volunteered to be bled from 18 to 24 months after vaccination. Ninety-eight percent (303/ 308) still had titers equal to or greater than 0.1 IU. The findings in three representative clinical subtrials in which neutralizing antibody titers are presented only for persons from whom successive blood samples were obtained at each indicated time are shown in Table 2. Successive blood samples were obtained from 86 percent (94/109), 74 percent (55/74), and 39 percent (34/88) of volunteers initially enrolled in the respective trials. Two weeks after the third and final injection of RVA, median RFFIT titers in the three subtrials were 6.4, 5.4 and 5.4 IU, respectively. All recipients in these subtrials had neutralizing antibody at two weeks and, in those tested, at six months after vaccination. However, neutralizing antibody titers six months after vaccination were lower than those at two weeks. Eighteen months to two years post-vaccination, median RFFIT titers were from to 0.3 to 1.2 IU and 261/271 (96 percent) of the volunteers had titers equal to or greater than 0.1 IU. Discussion The findings summarized in the present study show that the seroconversion rate after pre-exposure vaccination with RVA, given by the currently recommended three dose schedules, approximated 100 percent. However, the duration of the antibody response after initial pre-exposure rabies immunization is as important a concern as the seroconversion rate in evaluating immune responses to rabies vaccines because neutralizing antibody, actively induced by vaccination or passively acquired, is a key factor in protection against rabies infection.69 Yet, determination of the duration of responses to vaccination in sizable populations is complicated by reason of attrition of volunteers. Attrition rates at six months and at nine to 14 months in this study were 9 percent and 23 percent, respectively; these rates probably have little effect on the interpretation of the results in view of the finding that 94 percent of recipients or more had titers equal to or greater than 0.1 IU. On the other hand, even though the attrition rate for those bled 18 months to two years after vaccination was 48 percent, the percent of volunteers showing neutralizing antibody at that time is considered a good approximation of persistence of antibody because titers at two weeks in those who were bled later did not appear different than those in persons who were not bled at the later time. Although RVA and human diploid cell culture vaccine (HDCV) have not been compared to each other in concurrent clinical trials, the seroconversion rate, persistence of rabies AJPH April 1990, Vol. 80, No. 4
neutralizing antibody, and adverse reactions after pre-exposure immunization with RVA appear practically the same as those obtained with HDCV.2"l'9 ACKNOWLEDGMENTS The author wishes to acknowledge the contributions of Dr. N. McCullough, Michigan State University, East Lansing, MI (deceased); Drs. L.J. Swango and D. Oleson, Auburn University, Auburn, AL; Dr. C. Smith and Mrs. Elaine Pratt, Ohio State University, Columbus OH; Dr. C. Goswick and Mrs. Mary Scott, Texas A&M University, College Station, TX, for contributions to this study.
REFERENCES 1. Burgoyne GH, Kajiya KD, Brown DW, Mitchell JR: Rhesus diploid rabies vaccine (adsorbed): A new rabies vaccine using FRhL-2 cells. J Infect Dis 1985; 152:204-210. 2. Berlin BS, Mitchell JR, Burgoyne GH, et al: A new rabies vaccine (Adsorbed): Results of initial clinical studies of preexposure vaccination. JAMA 1982; 247:1726-1728. 3. Immunization Practices Advisory Committee (ACIP): Rabies prevention-United States, 1984. MMWR 1984; 33:393-402. 4. Smith JS, Yager PA, Baer GM: A rapid reproducible test for determining rabies neutralizing antibody. Bull WHO 1973; 48:535-541. 5. WHO Expert Committee on Rabies, 7th Report. WHO Technical Report Series 709. Geneva: WHO, 1984. 6. Wiktor TJ: Dynamics of rabies infection. In: International Symposium on Rabies. Symp Series Immunobiol Standard 1966; 1:65-80. 7. Karliner JS, Belavel GS: Incidence of reactions following administration of antirabies serum. JAMA 1965; 193:359-362. 8. Celis E, Wiktor TJ, Dietzchold B, Koprowski H: Amplification of rabies virus induced stimulation of human T-cell lines and clones by antigenspecific antibodies. J Virol 1985; 56:426-433. 9. Turner GS: Immune response after rabies vaccination: Basic aspects. An Institut Pasteur/Virology 1985; 136E:453-460. 10. Wiktor TJ, Plotkin SA, Koprowski H: Development and clinical trials of the new human rabies vaccine of tissue culture (human diploid cell) Origin. Dev Biol Standard 1978; 40:3-9. 11. Plotkin SA, Wiktor TJ, Koprowski H, et al: Immunization schedules for the new human diploid rabies vaccine. J Epidemiol 1976; 103:75-80. 12. Turner GS, Nicholson KG, Tyrrell DAJ, et al: Evaluation of a human diploid cell strain rabies vaccine: Final report of a three year study of pre-exposure immunization. J Hyg (Cambridge) 1982; 89:101-110. 13. Ajjan N, Soulebot JP, Stellman C, et al: Resultats de la vaccination antirabique preventive par le vaccin inactive concentre souche rabies PM/WI-38-1503-3M cultivee sur cellules diploides humaines. Dev Biol Standard 1978; 40:89-100. 14. Kuwert EK, Marcus I, Hoher PG: Neutralizing and complement-fixing antibody responses in pre- and post-exposure vaccines to a rabies vaccine produced in human diploid cells. J Biol Standard 1976; 4:249-262. 15. Cox JH, Schneider LG: Prophylactic immunization of humans against rabies by intradermal inoculation of human diploid cell culture vaccine. J Clin Microbiol 1976; 3:96-101. 16. Roumaintzeff M, Ajjan N, Vincent-Falquet JC: Experience with preexposure rabies vaccination. Rev Infect Dis 1988; 10 (suppl 4):S751-S757. 17. Rosanoff E, Tint H: Responses to human diploid cell rabies vaccine: Neutralizing antibody responses of vaccine receiving booster doses of human diploid cell rabies vaccine. Am J Epidemiol 1979; 110:322-327.
477
PUBLIC HEALTH BRIEFS 18. Dressen DW, Kemp DT, Brown J, Brown WJ: Antibody response to a single intradermal booster dose of rabies human diploid cell vaccine. JAVMA 1983; 183:1468-1469.
19. Bernard KW, Mallonee J, Wright JC, et al: Preexposure immunization with intradermal human diploid cell rabies vaccine. JAMA 1987; 257:10561063.
Health Effects of a Thorium Waste Disposal Site G. REZA NAJEM, MD, PHD, Abstract: A case-control study of 112 households residing in the vicinity of a thorium waste disposal site found a higher prevalence of birth defects (RR 2.1) and liver diseases (RR 2.3) among exposed than the unexposed group. The numbers were quite small and the confidence intervals wide, however, so that no definite conclusions can be drawn from these data. (Am J Public Health 1990; 80:478480.)
Introduction Several studies have appeared in the medical literature analyzing possible adverse health effects for persons living in the vicinity of hazardous waste disposal sites.'-3 To our knowledge there is no published study in which the health effects of a thorium waste disposal site (TWDS) on the general population have been investigated, except for a community-based study in China.4 That study found no deleterious health effects from exposure to thorium, but had very low statistical power. The main concern about the possible biological effects of thorium (Th) with a half life of 1.4 x 1010 years is based on its radioactive characteristics and isotopes.5 Thorium232 is the parent of various radio-isotopes including 228Ra (radium), 228Ac (actinium), 228Th, 224Ra, and 220Rn (radon)5, Current interest is based in part on increased use of thorium as an energy source, e.g., in reactors using 232Th to produce 233U.6 Industrial and mining exposure to thorium have resulted in an increased incidence of lung cancer, pancreatic cancer, colorectal cancers, chronic respiratory diseases, liver damage, and other serious illnesses.7-9 Skeletal sarcomas, thorotrastomas, and sarcomas of the reticuloendo-thelial system have been reported from a study of patients receiving intravenous injections of thorotrast, a collodial solution of thorium oxide that was used as a contrast medium for diagnostic radiographic studies from the 1930s to the 1950s.'0 The purpose of this study was to conduct a survey of health effects of a thorium waste disposal site among members of the general population of Wayne, New Jersey, USA. Thorium Waste Disposal Site
The site is located on a 6.5 acre tract of land in Wayne Township, Passaic County in northern New Jersey, USA.* The population density in Wayne is 1,867.2 per square miles and annual per capita income is $7,725. "1 The thorium waste burial site lies within 100 feet of the sidewalk. Commercial Address reprint requests to G. Reza Najem, MD, PhD, Department of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School, 185 S. Orange Avenue, Newark, NJ 07103-2757. Ms. Voyce is with the New Jersey Institute of Technology, Newark. This paper, submitted to the Journal July 24, 1987, was revised and accepted for publication August 1, 1989. *New Jersey Department of Environmental Protection: Site Descriptions for Hazardous Waste Sites in New Jersey. Division of Waste Management, Hazardous Site Mitigation Administration, 1984/85. © 1990 American Journal of Public Health 0090-0036/90$1.50
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businesses, a nursing home, a school bus maintenance yard, and residential homes are adjacent to the site. A drainage ditch lies at the northern and eastern borders, and drains into a brook at the northeast corner of the burial field. The brook (a tributory to the Pompton River) flows through residential areas (copy of map available on request). Fresh water wetlands lie approximately 1,800 feet to the west of the thorium waste disposal site.* From 1948 until 1971, a company extracted thorium and rare earths from monazite ore, for usage by the Atomic Energy Commission.* During its active years, the plant waste was dumped in backyard sludge piles. The wastes have been buried only in the last few years, after spending over 20 years above the ground.** Surveys of the New Jersey Department of Environmental Protection showed readings of 40-1491 uR/hour (uR = micro-rad, micro being 10-6) in various regions classified as contaminated areas; Sheffield Brook contamination occurs within 10 meters of both sides. Soil samples revealed Thorium (232Th), Radium (238Ra) and Uranium (238Ur) in the contaminated regions. Water samples from Sheffield Brook and the drainage ditch showed mainly alpha and beta activity. Most of the air concentrations (ambient and indoor) were within the background radiation levels (approximately 150 mrem/year) The US Environmental Protection Agency (EPA) standard for home concentration is below 4 pCi/ liter.*** The residents of the households in the vicinity of the thorium waste disposal site and in the vicinity of contaminated Sheffield Brook have not been tested for radioactive materials uptake. Methods The exposed population included 76 households within three blocks adjoining the contaminated areas. The 76 comparison (unexposed) households included all houses located on about 9th and 10th blocks distance from the thorium waste disposal site and contaminated Sheffield Brook. Households were accepted for inclusion in the study if they had resided at the present address for at least five years. Eleven and 10 households of the exposed and unexposed groups, respectively, did not meet the criteria for eligibility, 10 and nine households, respectively, did not participate in the study due primarily to members not being at home at the time of scheduled interviews or having moved out without leaving forwarding addresses. Face-to-face interviews of all 112 households (362 members), using a structured questionnaire, were carried out by one interviewer who did not know exposure status; 32 household members who did not agree to a face-to-face **New Jersey Department of Environmental Protection. Unpublished data. ***US Environmental Protection Agency, Office of Radiation Programs, Washington, DC 20406. Further details on measurements of exposed areas are available on request to author (Najem). AJPH April 1990, Vol. 80, No. 4
