Chlorinated dioxins and dibenzofurans in human tissue from general populations: a selective review.

During the past decade a considerable amount of data has been generated concerning polychlorinated dibenzodioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in humans from many geographical locations. To organize these data in a useful fashion for environmental purposes and for consideration of human toxicity, selected portions of our data are presented in a somewhat atypical fashion, by percentage contribution of individual congeners to total PCDD/Fs in human tissue, and to the total dioxin equivalents (TEq). This is done to better characterize congener contributions from environmental contamination in various geographical regions at this time and health-related levels. To present the findings in a global perspective, data from widely different locations are presented including the United States, Germany, Vietnam, the former Soviet Union, Thailand, Cambodia, China, South Africa, and Guam.


Introduction
The first measurement ofdioxin in human tissues and food was reported in the early 1970s by Baughman (1,2). He measured 2,3,7,8-TCDD (T[CDD) in human milk and fish from the south of Vietnam from areas sprayed with Agent Orange, a mixture of phenoxyherbicides contaminated with dioxin. Human milk samples from the United States general population were used as controls. A level of 1450 ppt TCDD on a lipid basis was found in one woman's milk, levels between 200 and 400 ppt were found in other samples, and there were specimens from the same villages where no TCDD was measured at detection limits ranging from 29 to 429 ppt, lipid. Later in the 1970s, Rappe, Masuda and others reported human tissue levels ofpolychlorinated dioxins and dibenzofurans (PCDDs and PCDFs) (3)(4)(5). The first measurement ofdioxins and dibenzofutrans in potentially exposed American workers and the general public was reported in 1983 and published in 1985 (6,7). This documented dioxins and dibenzofurans in the blood and adipose tissue ofthe general public and also elevated PCDD/Fs in some exposed workers. With marked improvements in specificity and sensitivity, a large number of reports worldwide have described human tissue and food levels of these chemicals which, for the most part, are synthetic and of recent origin (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). This paper reviews recent findings in human tissues from a number of countries, which vary in level of industrialization. The geographic regions include North America, Europe, Asia, South Africa and a geographically isolated South Pacific island, Guam. This diverse and widespread geographical sampling presents evidence for the industrial origin of most dioxins and dibenzofurans and illustrates the use of dioxin levels in human tissue as a reflection of regional industrialization and environmental contamination. Evidence for industrial origin ofmost dioxins has also previously been demonstrated from environmental data (26)(27)(28)(29) and from human tissue measurements of frozen ancient Eskimo tissue compared to modem tissue (31,32). Food consumption is the primary form of human intake in these cases, specifically meat, milk, fish, and their by-products (18,(22)(23)(24)30). PCDD/F levels are presented for various organs of the body considered to be target organs for dioxin toxicity, and these levels are compared to adipose tissue, which, along with blood, is usually used as a signal tissue or reference for dioxin levels and estimates of body burden in potentially exposed persons.
However, the number of human organs that have been analyzed for dioxins at the present time is insufficient to characterize the levels and their ratios in human tissues. Dioxins are extremely toxic to many animal species and appear to be carcinogenic for humans as well as laboratory animals (33)(34)(35)(36)(37). For some dioxins, certain biochemical markers of exposure and sensitivity appear to have similar responses in humans and laboratory animals (38,39). It is possible that the levels currently found in human tissues may have health consequences for individuals or may cause increased rates of disease on a population basis. Most previous publications, including our own work (40), have described actual dioxin tissue levels, without detailed or congener pattern analysis by percentage, which is the focus of this paper. The data are compared in terms of both measured PCDD/F tissue congener levels and by dioxin toxic equivalents (41)(42)(43). The data are from the general population rather than from exposed populations. In many cases sample size is insufficient to generalize about populations; pooled samples are sometimes used in an attempt to increase sample size for each of these difficult and costly analyses. With a larger sample size and a more systematic sampling in the future, along with a decrease in the costs for dioxin analysis and an increase in laboratory capacity, these values may change andbe found not representative of general populations ofthese specific geographical areas. At this time, however, they do constitute a substantial amount ofthe data available by countries, and so seem reasonable to present and use, despite potential limitations with regard to being adequately representative of the adult populations for the countries involved. Also, as environmental contamination decreases, it is hoped and expected that PCDD/F tissue levels in the general population will also decrease gradually over time. Because of the extreme persistence of dioxins and related chemicals in the environment, this decrease may take a very long time. A recent Environmental Protection Agency report on human tissue levels in the United States suggests that such a decrease in dioxin body burden may have begun this past decade (44).

Methods
The analytic methods used have been previously described and will only be referenced in this paper (16,31,32,46,47). All laboratories reporting data in this paper successfully participated in the recent World Health Organization's interlaboratory validation study for human milk or blood (45).

Results and Discussion
Dioxin Levels in Blood Tables 1 and 2 present blood lipid dioxin and dibenzofuran levels from locations in Vietnam, two from the south (Ho Chi Minh City and Dong Nai), and one from the north (Hanoi); Germany; the United States; St Petersburg (formerly Leningrad), in the European part of the Soviet Union, Baikalsk, on the shores of Lake Baikal, a small city in eastern Siberia in Russian Asia; and Guam, an island in the South Pacific Ocean (48). The data represent the mean of individual analyses from Germany and Guam and values from pooled blood for the other areas.
The data are presented by actual levels as well as by percent contribution from each congener to the total levels and also by percent contribution in dioxin toxic equivalents (TEqs) using the current international units (41)(42)(43). For the actual levels, the more industrialized countries or parts of countries can be identified readily by the total dioxin levels. In the former USSR, total PCDD values are low in both St. Petersburg (130 ppt) and Baikalsk (88 ppt), as in the case for Hanoi, with a value of 126 ppt. Levels are higher in Germany, where the total PCDD is 788 ppt, in the United States (1499 ppt), in Guam (1810 ppt), in Dong Nai (1938 ppt), and in Ho Chi Minh City (1087 ppt). In the south of Vietnam, elevated dioxin levels are consistent with former French and American industrialization and use of chemicals, whereas in Guam, imported food from more industrial areas, such as the United States and Japan, may be causing a more typical industrial pattern of PCDD/Fs in human tissue. Guam is also the home of a U.S. naval and air base, which could also contribute to the toxic chemical burden. Dibenzofuran levels are highest at 133 ppt in Dong Nai, Vietnam, surprisingly, followed by Germany (98 ppt), the United States (92 ppt), and the lowest levels are from Hanoi (41 ppt), and St. Petersburg (31 ppt). It is noteworthy and somewhat surprising that St. Petersburg, a European city, has such low levels.
The values for the toxic equivalents in Table 2 for whole blood show Dong Nai and the U.S. values are highest for dioxins, 31 and 30 ppt, respectively, with Guam at 24 and Germany at 20 ppt. The lowest value of 6 ppt is found in Hanoi, with Baikalsk (8 ppt) and St. Petersburg (11 ppt) in the same range. For dibenzofuran TEqs, the German value is highest at 22 ppt, followed by Dong Nai (18 ppt), Ho Chi Minh City (14 ppt), the United States (11 ppt), Baikalsk (10 ppt), and Guam (8 ppt). Hanoi and St.
Petersburg both have a value of 6 ppt.
Tables 1 and 2 also list the percent contribution from the individual congeners to the total levels. For Ho Chi Minh City, an area from the south of Vietnam formerly sprayed with Agent Orange, it is most striking that the percentage of the total PCDD/Fs from TCDD is now only 0.29% and, expressed in dioxin toxic equivalents, only 12%. Octa (OCDD), which is usually the congener found in the largest amount in human  (48). Baikalsk and St. Petersburg are cities in the eastern and western former USSR, respectively. Samples are from whole blood, except for the U.S. sample, which is from plasma. Samples are from pooled blood except Germany, which is the mean of 102 individual analyses.
tissues for most countries, for unknown reasons, provides almost from 1962 to 1970 in Vietnam. For that reason, levels of 80% of the total PCDD/F but only 3.3% ofthe toxicity using cur-2,3,7,8-TCDD in human tissue collected in Vietnam between rent toxicity estimates for the Ho Chi Minh City blood. A larger 1984 to 1990 are probably, on average, lower than was previously portion of the toxicity is contributed by the 5and 6-chlorinated the case. dioxin and dibenzofuran congeners. The relatively little dis-In Dong Nai province, also a heavily Agent Orange-sprayed cussed, but toxic 2,3,4,7,8-PeCDF, makes a substantial contribuarea in the south of Vietnam, TCDD levels found in the 1980s tion to dioxin toxicity here, providing almost 38 % of the total were quite high, contributing about 25 % to the total PCDD/F dioxin toxic equivalents. Although total dioxins contribute 93% toxicity. Although the congener totals for dioxins and dibenand dibenzofurans 7 % to total levels, they each contribute 50% zofurans in Dong Nai are similar to the Ho Chi Minh City levels, ofthe dioxin toxic equivalents in the specimen from Ho Chi Minh approximately 94 and 6%, respectively, the dioxin toxic City. It should be noted that Agent Orange spraying occurred equivalent pattern reflects a larger contribution from TCDD.
Here, the dioxin toxic equivalent contribution from the dioxins are 63 % and, from dibenzofurans, 37 %.
In Hanoi, in the north ofVietnam where little industry is present and where no Agent Orange was sprayed, the total PCDD/F levels are quite low, at 167 ppt, compared with the 1000-2000-ppt levels found in the blood specimen from the south ofVietnam. However, the relative dioxin and dibenzofuran toxicity resembles that seen in the specimens from Ho Chi Minh in that almost half, 47 %, is from PCDDs and 53 % is from PCDFs. A somewhat unusual pattern exists in that there is more dioxinlike toxicity from the dibenzofurans than from thedioxins themselves, although the dioxins predominate in absolute amount, 126 pptcompared to 41 ppt.
Germany and the United States represent typical industrial countries with massive production and disposal of synthetic chemicals. Total dioxins and dibenzofurans in human tissue from each of these countries have previously been noted to be relatively similar in amount. Here in these samples, the total dibenzofuran levels are similar, but there is higher dioxin content in the American blood, to a considerable extent due to the OCDD. The finding that the 2,3,4,7,8-penta (Pe CDF) level is markedly higher in German blood (a typical European finding), with 37 ppt, than in the U.S. sample, with 13 ppt, is characteristic and worthy of note. This converts to a 44 (German) versus 16% (U.S.) contribution to the total in dioxin toxic equivalents for this congener. For total dibenzofuran TEq, toxicity is higher in Germany when compared to the United States, 52 versus 27%, respectively. TCDD TEq, however, plays a relatively minor role in each country, with values of 9 and 13 % in German and American blood, respectively. This finding suggests that too much attention may have historically been given to the well-known 2,3,7,8-TCDD congener as compared with other PCDDs and PCDFs, which contribute far more to the total toxicity.
The former Soviet Union is of interest for a number of reasons. It was a large country, with varying degrees of industrialization that have been rapid and relatively recent, especially in Siberia. If airborne dioxins and dibenzofurans play a major role in environmental levels, we would expect human tissue levels to be similar in geographically remote areas. For that reason, we chose to sample blood from Baikalsk, located far into Asiatic Siberia, on the southern bank of remote Lake Baikal, and St. Petersburg, in Europe, several thousand miles west ofBaikalsk. In Baikalsk, the total PCDD/PCDF levels are low, 137 ppt, with a PCDD/ PCDF ratio of about 2:1, whereas in St. Petersburg, the total PCDD/F level was also low at 161 ppt, but with a PCDD/PCDF ratio of approximately 4:1. These levels are considerably lower than those seen in most industrial locations.
In Guam, a relatively isolated island in the South Pacific Ocean, almost all the PCDD/F congeners detected are dioxins (1810 ppt) which contribute 96 % to the total, of which 81.1% is from OCDD, while dibenzofurans (80 ppt) contribute only 4 %. The total PCDD/F level of 1,890 ppt is the second highest in this series. This pattern holds for the toxic equivalents also, with 75% from dioxins and 25 % from dibenzofurans. Guamanians' blood congener total and TEqs are similar to the continental United States, which is the source ofmost oftheir food and where some reside periodically.
Figures 1 and 2 present the total dioxin and dibenzofuran levels and the total TEq values in graphical form, for ease in visualization and comparison. Table 3 compares blood dioxin levels from samples collected from 1980 to 1990 from 10 locations in the north, central, and south regions ofVietnam, which, as noted previously, is the country with the most extensive known dioxin contamination (from Agent Orange). The highest 2,3,7,8-TCDD blood level is 28 ppt from Binh Hoa in the south followed by 18 and 15 ppt from Da Nang and A Luoi, respectively, which are both in central Vietnam. Dong Nai and Ma Da Forest in the south both have the same level of 12 ppt. In the central region, the sample from Hue has 11 ppt, and the remaining locations have levels of 9.5, 6.8, and 3.4 ppt. Hanoi in the north has the lowest level, as expected, of less than 2.4 ppt. For total levels, Dong Nai has the highest dioxin level of 1,938 ppt, followed by 1,529 ppt in Da Nang. Hanoi has the lowest total dioxin level of 126 ppt.
For the dibenzofurans, there is a different pattern, with Da Nang and Hue from the central region having the highest total of 315 and 265 ppt, respectively; the lowest PCDF levels are in Tay Ninh, with 26, and Ma Da Forest with 29 ppt. The northern specimens have a higher dibenzofuran level of41 ppt. The highest total PCDD/Fs TEq value is 77 for Da Nang, followed by 57 for Hue, and 12 ppt from Hanoi is the lowest value found in Vietnam.
The remaining values range from 49 to 16 ppt. These values compare with the higher total estimated TEqs ranging between 200 and 1500 ppt in Vietnamese milk from the original Baughman specimens collected in 1970 by Constable and Meselson, primarily reflecting contamination by Agent Orange (1).

Dioxin Levels in Milk
A second type ofsample frequently used for measuring dioxins in human tissue is milk. Table 4 presents the percent contribution by congener from human milk samples. Vietnam specimens are from Hanoi in the north, Da Nang in Central Vietnam, and Dong Nai Province in the south. Phnom Penh, Cambodia, a markedly nonindustrial country, and Bangkok, in Thailand, a country undergoing rapid industrialization, complete the three Asian countries represented. Germany in Europe and the United States in North America represent the more industrialized countries. Siberia, representing an Asian portion ofthe former USSR, and South Africa, where we have samples from both the black and the white population, represent areas of less industrialization. Pooled samples were usually used because oftime and cost constraints, as well as the desire to increase sample size from each geographical area (49)(50)(51).
The contribution of TCDD, the most toxic dioxin, to total PCDD/Fs varies from 0.33% in Thailand to 4.3% in Dong Nai. Contribution to TEqs is highest at 38.5% in Dong Nai, an Agent Orange-sprayed province in the south ofVietnam, and 10-23.9% for the other countries. 1,2,3,7,8-PeCDD values are more uniform, with contribution to the total ranging from 1.2 to 3.3 % and the TEq percent contribution varying from 13.8 % in Dong Nai and Siberia to 26.7% in Cambodia. Among the dibenzofurans in milk, as is typical for most human tissue studied to date, especially from European countries, 2,3,4,7,8-PeCDF is most striking in its contribution to TEqs, with values ranging from 44.8 % in Germany and 41.9% in Thailand to 21.8 % and 12% in the samples from South Africa. For HxCDDs, South Africa's black population sample has the highest contribution (9.2%) and Thailand has the lowest (2.5%). The HxCDFs have  The findings from South Africa are of interest because of the difference in levels between the black population and the white population. The values are usually lower for the black population than the white. This is consistent with the idea ofthe white population having a dietary intake ofhigher quality and quantity consisting ofmore meat, fish, and milk products, thus having higher dioxin and dibenzofuran levels.    (1) son, a pie graph presentation by individual countries ofcongener contribution to the total dioxin toxic equivalents in adipose tissue from general populations is shown in Figure 3. This is more representative of toxicity (rather than environmental contamination) than presentations ofanalytic data, but is subject to change  (Continued on next page) as dioxin and dibsnzofuran congeners are assigned different values when new information concerning toxicity, pharmacokinetics in humans, or toxicity for specific end points becomes available. It is useful, however, to give an approximation of human toxicity contributed by the congeners, just as previous data and presentation usually reflected total levels of chemicals and percentage oftotal PCDD/Fs in the environment. For the United States, we find 2,3,7,8-TCDD contributing 29%, HxCDD 28%, PeCDD 17%, and PeCDF 14%. In Germany, we see a somewhat different pattern, with PeCDF 52%, HxCDDs 16%, and TCDD 7% of total TEqs (52).
In Japan, we found TCDD contributing 18%, with  HxCDDs, 18% from HxCDF, and 17% each from PeCDD and PeCDF. In Canada, the percentage is similar to the United States. TCDD contributes 20% of the TEqs, with HxCDD 27%, PeCDF 24 %, PeCDD 16%, HpCDF 1% and OCDD, the most plentiful congener, contributes only 3 % (11). Results for Vietnam are presented for the north and south of that nation. The persons sampled from the south ofVietnam lived in provinces where Agent Orange spraying occurred in the past, but were otherwise selected from the general population. TCDD contributes 53% ofthe TEqs in this series, followedby 16% from HxCDD, 13% PeCDD, 8% HxCDF, 3% TCDF and HpCDD, and 2 % from OCDD. In the north ofVietnam, by contrast, with its much lower levels of PCDD/Fs, TCDD contributes only 17% oftotal TEqs, whereas 25 % is from HxCDF, 18 % from HxCDD, a much higher than usual 16% is from TCDF, 14% is from PeCDD, 7% from HpCDD, and only 1% is from OCDD (9,53,54). China, where total dioxin and dibenzofuran levels are quite low, has the largest TEq contribution of 46% from PeCDF, followed by 22% from PeCDD, 14% from HxCDF, 10% from HxCDD, 2% from HpCDD, and a low 1% from OCDD, the most plentiful but least toxic congener (11).
Dioxin Levels in Stillborn, Ancient, and Modern Human Livers Figure 4A presents levels oftotal dioxins recently measured in livers of three stillborn infants (55), one ancient adult found frozen in Alaska (32), and three modern adults from the United States (56) in order to contrast the markedly higher levels of dioxins and dibenzofurans currently found in adults, primarily from industrial sources, and to highlight the increase in dioxin body burden seen in adults as compared to children at birth. Findings of low levels in stillborns reflects transplacental transfer due to unavoidable intake, so long as environmental contamination persists. Figure 4B presents the same data converted to dioxin toxic equivalents to provide a reference from a toxicologic standpoint. It is interesting to note that the modern stillborn liver dioxin TEq of 10 is quite similar to that found in ancient adult livers, 14 ppt, on a lipid basis.   CTotals are rounded.

Dioxin Levels in Multiple Organs: Autopsy Specimen
It has recently become useful to estimate body burden and to make decisions as to exposure following special incidents, such as Agent Orange or industrial chemical contamination, by reporting adipose tissue or blood-lipid dioxin values. However, this does not provide target organ PCDD or PCDF levels. For this reason, congener contribution to total PCDD/F measurement and to total TEqs are presented in Tables 5 and 6, respectively, as mean values from two autopsies (9,56) performed on New York State residents in the 1980s. The values are presented on a wet-weight basis, but lipid values are provided to permit conversions. Further work is needed to increase the sample size to permit adequate tissue level characterization.
Comparison of Dioxin Levels in Blood, Milk, and Adipose Tissue Data for human tissue dioxin levels are obtained primarily from human blood, adipose tissue, and human milk, as discussed in this paper. Table 7 presents a comparison oftissue levels from blood, adipose tissue, and milk from the general population of the United States (48,49,52). We found in these samples that blood has the highest total PCDD/F levels in absolute values and in TEq values. The levels are 1591, 590, and 356 ppt for absolute values for blood, adipose tissue, and milk, respectively and 41, 24, and 17 ppt, respectively, for TEq totals. It is also noteworthy that milk has the lowest levels in almost every instance except when it has the identical value with adipose of 5 ppt for total PCDF TEq. These observations have been made by others as well during the past few years. These data are from general population data, not from the same individuals. Figure 5 presents the same data in a graphical form for ease of visualization and comparison.
Particularly striking in our experience, as shown in the data presented here, is the observation that dioxin congeners fiequently constitute approximately 90% of the total measured dioxins and dibenzofurans. But considering dioxin contribution to total toxic equivalents, they constitute approximately 61% of toxicity, with dibenzofuran contribution varying from nondetected to 39%, in the various tissues studied. In the case ofOCDD, which contributes the most to the actual amounts measured, were OCDD to be given a more conservative TEq of0.01 rather than 0.001, which could bejustified using OCDDs highest toxic outcome (57,58), the TEq from dioxins as well as total TEq would be higher.

Summary and Conclusions
We have reviewed what we believe to be relatively representative data ofthat available from the general populations on dioxin and dibenzofuran levels in human blood, fat, milk, and other selected organ or tissue samples from a number of countries worldwide. Included in these data are ancient frozen human tissue and modern human tissue from stillborn infants as well as adult tissue for purposes of comparison.
The data have been manipulated, in some cases, to provide the percentage that a given congener, such as 2,3,7,8-TCDD, contributes to the total PCDD/Fs measured. In other cases, conversion to TEqs has been performed, followed by a numerical or graphical presentation ofthe contribution by congener to the total estimated toxicity of all measured congeners.
With present techniques, we can usually detect between 14 and 16 2,3,7,8 toxic chlorine-substituted congeners in human tissue. In some locations, as in less industrialized regions such as China, Thailand, Cambodia, and the north ofVietnam, we find relatively low levels ofdioxins and dibenzofurans, in the range of 100 -160 ppt on a lipid basis in blood or adipose tissue. Human tissue from more industrial areas usually has higher tissue dioxin levels, for example, the U.S. and German values of 1,591 and 886 ppt, respectively, for total PCDD/F. We are sometimes surprised by other levels: in remote Dong Nai Province in the south ofVietnam, total PCDD/F in blood lipid was found to be 2071 ppt, and in a remote South Pacific Ocean island, Guam, we ibund average levels of 1890 ppt, to a considerable extent due to high OCDD levels. The source of industrial contamination, which contributed to relatively elevated human tissue levels, presumably through consumption ofcontaminated meat, milk, fish, and their   19 12 Germany, 42% in Baikalsk, 38% in Ho Chi Minh City, and 36% Total PCDF TEq 11 5 5 in Hanoi).
Total PCDD/F TEqb 41 24 17 Variations in general population dioxin levels appear to be al. (4),fo mlkse Schecteret 3l.5(49)~g reater than is the case for the dibenzofurans, which are usual-  contamination in the past, such as the spraying ofpart ofVietnam with herbicide contaminated with 2,3,7,8-TCDD, elevated TCDD levels may be found in humans decades later. The source ofmost dioxins and dibenzofurans is not known at this time, so amounts of dioxins and dibenzofurans in globally different regions may vary without apparent explanation. Levels vary considerably in ash from municipal incinerators and in soot from PCB transformer fires, for example. The question as to whether chlorinated dioxin and dibenzofurans existed before industrialization and formation of synthetic chemicals (62) is addressed in two ways by human tissue data. The higher levels of PCDD/Fs found in tissue from industrial countries and lower levels in samples from less industrial countries suggests industrial origin for most PCDD/Fs. Compared to present adult levels, the finding of quite low levels of PCDD/Fs in frozen ancient Eskimo tissue from the United States, similar to levels found in stillborns at the present time, is also consistent with an anthropogenic origin ofalmost all dioxins and dibenzofurans in the environment. This is also consistent with sediment data analyzed by time ofdeposition or by location (26)(27)(28)(29).
Autopsy data are beginning to provide tissue-specific dioxin levels, which will make it possible to extrapolate blood dioxin levels, usually the tissue ofchoice for most patients, with target organ tissue levels. However, autopsy data are limited at this time (9). Another question of interpretation from blood dioxin measurements is the effect on blood, fat, and other organs of wasting, which occurs in terminal cancer patients, AIDS patients, and in certain other disease states. In a similar fashion, fasting may or may not mobilize body stores and increase blood dioxin levels. Answers to these questions require further study before body burden or target tissue dose can easily be determined from blood or fat measurement.
The past decade has witnessed an explosion of research on human tissue chlorinated dioxin and dibenzofuran levels. This has been driven by markedly improved chemical techniques. With these techniques and with an increase in capable laboratories and a decrease in costs, the next decade should provide a wealth of useful environmental and health data relating to the dioxins, especially regarding those dioxin levels in human tissue that are causally related to disease. Some of the studies cited here have been made possible by the generous assistance of the Christopher Reynolds Foundation, the Samuel Rubin Foundation, the CS Fund, Church WMrld Service, and CIDSE. The expert technical assistance in preparation ofthis manuscript is due to Ruth Stento, Karan Charles, Deborah Suess, and Diann Yannantuono. Most ofall, we thank the persons whose tissues were used to obtain the dioxin data.