1 15 10 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 032 Folder The folder containing the original item. 0614 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Duggan, R. E. H. C. Barry L. Y. Johnson Source A related resource from which the described resource is derived Science Date A point or period of time associated with an event in the lifecycle of the resource January 7 1966 Title A name given to the resource Pesticide Residues in Total-Diet Samples Subject The topic of the resource dietary exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 032 Folder The folder containing the original item. 0615 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Duggan, R. E. J. R. Weatherwax Source A related resource from which the described resource is derived Science Date A point or period of time associated with an event in the lifecycle of the resource September 1 1967 Title A name given to the resource Dietary Intake of Pesticide Chemicals Subject The topic of the resource dietary exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 032 Folder The folder containing the original item. 0616 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Duggan, R. E. P. E. Corneliussen Source A related resource from which the described resource is derived Pesticides Monitoring Journal Date A point or period of time associated with an event in the lifecycle of the resource 1972-03-01 Title A name given to the resource Dietary Intake of Pesticide Chemicals in the United States (III), June 1968-April 1970 Subject The topic of the resource dietary exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 039 Folder The folder containing the original item. 0877 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Longstreth, Janice D. Judith M. Hushon Description An account of the resource Corporate Author: Dynamac Corporation, Enviro Control Division, Rockville, Maryland Source A related resource from which the described resource is derived Human and Environmental Risk of Chlorinated Dioxins and Related Compounds Date A point or period of time associated with an event in the lifecycle of the resource 1983 Title A name given to the resource Risk Assessment for 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) Subject The topic of the resource dietary exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 040 Folder The folder containing the original item. 0901 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Meselson, Matthew Patrick O'Keefe Robert Baughman Date A point or period of time associated with an event in the lifecycle of the resource March 3 1978 Title A name given to the resource Typescript: The Evaluation of Possible Health Hazards from TCDD in the Environment Subject The topic of the resource dioxin animal testing dietary exposure health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 040 Folder The folder containing the original item. 0902 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Meselson, Matthew Date A point or period of time associated with an event in the lifecycle of the resource 1978-02-01 Title A name given to the resource Typescript: Comments on the Evaluation of Possible Health Hazards from TCDD in the Environment Subject The topic of the resource dioxin animal testing dietary exposure health studies ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 040 Folder The folder containing the original item. 0920 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Murai, Yoshiyuki Yoshigoro Kuroiwa Source A related resource from which the described resource is derived Neurology Date A point or period of time associated with an event in the lifecycle of the resource 1971-11-01 Title A name given to the resource Peripheral Neuropathy in Chlorobiphenyl Poisoning Subject The topic of the resource health studies dietary exposure human ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 042 Folder The folder containing the original item. 1000 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Reggiani, G. Description An account of the resource Corporate Author: International Academy of Environmental Safety. International Society of Ecotoxicology and Environmental Safety. Source A related resource from which the described resource is derived Accidental Exposure to Dioxins: Human Health Aspects Date A point or period of time associated with an event in the lifecycle of the resource 1983 Title A name given to the resource An Overview on the Health Effects of Halogenated Dioxins and Related Compounds - The Yusho and Taiwan Episodes Subject The topic of the resource dietary exposure Southeast Asia health effects herbicide toxicology ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 044 Folder The folder containing the original item. 1066 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Somers, E. V.M. Douglas Source A related resource from which the described resource is derived Human and Environmental Risk of Chlorinated Dioxins and Related Compounds Date A point or period of time associated with an event in the lifecycle of the resource 1983 Title A name given to the resource Dioxins and Related Compounds as Issues of International Concern Subject The topic of the resource air pollution dietary exposure herbicide regulation environmental hygiene ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/feedee5138378232713d4506b35a7e95.pdf 4eecc61c9623b6fbf2364968db6eb841 PDF Text Text Item ID Number °1353 Author Barnes, Donald G. Corporate Author Report/Article TltlO Memorandum: FDA Risk Assessment for Higher Chlorinated Dibenzo-p-dioxins, from Donald G. Barnes to Alvin Young and others, May 13, 1983 Journal/Book Title Year 0000 Month/Day Color D Number of limps 21 DeSCTlptOn Notes Includes as an attachment this article: "The Use of Epidemiology in the Regulation of Dioxins in Food Supply," Regulatory Toxicology and Pharmacology, 1, 379-387(1981). Thursday, May 03, 2001 Page 1353 of 1403 �UNITED STATES ENVIRONMENTAL PROTECTION AGENCY tp WASHINGTON, D.C. 20460 < 1 3 1983 OFFICE OF PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM TO: Addressees SUBJECT: FDA Risk Assessment for Higher Chlorinated Dibenzo-p-dioxins Attached is a recently prepared risk assessment by the Food and Drug Administration for hexa-, hepta- and octachlorodibenzo-p-dioxins in chicken eggs. I believe the analysis presented here is an interesting one and could provide fodder for a future first Friday feed. Donald G. Barnes, Ph.D. Senior Science Advisor to the Assistant Administrator for Pesticidees and Toxi-'C, .Sujsst-.ances Attachment Addressees : Lisa Barrera Pat Roberts Judy Bellin David Vanormer Priscilla Holtzclaw Bob McGaughy (/Al Young Carl Keller A-101 '-' A-132 WH-565 TS-769C WH-548D RD-689 f Veterans Adm. <£— T4 NIEHS �DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Memorandum Date April 29, 1983 Prom Acting Chief, Contaminants & Natural Toxicants Evaluation Branch (HFF-159) Subject Levels of Concern for Hexa- (HCDD), Hepta- (HpCDD) and Octachlorodibenzo-p-dioxins (XDD) in Chicken and Eggs To Mr. John Taylor Director, Division of Guidance (HFF-310) Through: Dr. Gary Flamm Acting, Associate Director for Toxicological Sciences (HFF-100) As a result of concerns for higher chlorinated dioxin contamination of chickens and eggs the Texas Department of Health has requested "that FDA provide guidance as to health or regulatory significance as well as action guidance" (W. Remle Grove, see attachment # 1). In response to this request, as submitted through DRG, we have reviewed the available information on the toxicity of several dioxin congeners. Based on this review we are suggesting the following levels of concern (LOG) for these substances in chicken and eggs. Levels of Concern^/ HCDD HpCDD OCDD 300 parts per trillion 500 parts per trillion 3 parts per million a/ Because the amounts of chicken and eggs consumed are similar, a uniform level of concern for the respective contaminants can be applied to each food item. The rationale, biological and/or toxicological end-points and factors utilized in the development of the above LX are identified in subsequent pages and attachments. It is important to recognize that the available literature from which these levels were derived is limited. We emphasize that these levels apply only to the present situation in Texas .and do not have general applicability to contamination by the dioxin congeners HCDD, HpCDD and OCDD in food. In this situation the various isomers of each congener will not be dealt with individually but rather as a group (e.g., as congeners). This is so because of a lack of- a) biological and/or toxicological studies on specific isomers, and b) knowledge of the presence of individual isomers involved in the Texas situation. It should also be noted that while the carcinogenicity of these congeners was assssed, where specific studies were available, the potential exposure to them in the Texas incident is considered to be of a relatively �-2- short duration (e.g.,-possibly several weeks up to several months). Therefore, carcinogenic potential was not used as the toxicological determinant in deriving the LXs for dioxins in chicken and eggs. It is equally important to recognize that other toxic manifestations, such as reproductive and/or teratogenic effects, may result from pulse (single) or short-term (days to weeks) exposures to dioxins such as the HCDD congener. It is the concern for these non-carcinogenic effects which serves as the basis for our evaluation, again since lifetime exposure is not an issue. Since the tetrachlorodibenzo-p-dioxin (TCDD) congener is the best studied and most toxic member of this class of toxicants, the health assessment performed on tha presence of TCDD in freshwater fish from various areas of the Great Lakes (F. Cordle, Reg. Tox. Pharm., 1;379-387, 1981; see attachment # 2) will be used as the basis for the establishment of LXs for HCDD, HpCDD and OCDD. In that assessment it was determined from a multi-generation reproduction study in rats that the no-effect level for TCDD was 1 nanogram (ng)/kg b.w./day. In keeping with these findings, a concern level of 25 ppt TCDD in fish was recommended by FDA to State officials. The value of 25 ppt TCDD and a fish consumption value of 37 g/day (99th percentile) is used in the present assessment to derive maximum daily intakes for the other dioxins (HCDD, HpCDD and OCDD) based on appropriate safety factors and their biological and/or' toxicological potency in relation to TCDD. In order to evaluate the relative biological/toxicological potency of these toxicants, several different types of studies were assessed. A number of studies have shown that there is a distinct relationship between the ability of the dioxins to elicit several of their toxic and/or biological manifestations and to bind to a cytosolic-receptor. These studies have shown that for the dioxins to produce any appreciable degree of toxicological and/or biological activity the four lateral ring positions must be occupied by chlorine atoms and at least one ring position must be unsubstituted. The comparative induction of aryl hydrocarbon hydroxylase (AHH) by a number of dioxins, including TCDD, HCDD, HpCDD and XDD has been studied in rat hepatoma cell cultures by J. Bradlaw and co-workers (Fd. Cosmet. Tox., .18:627-635, 1980). Their studies showed that the relative potency of the most active congeners of HCDD, HpCDD and XDD were 1/10, 1/200 and 1/25,000 of that of TCDD (relative potency of 1), respectively. In similar studies performed ty A. Poland and associates (Mole. Pharm., 2-736-747, 1973) on AHH induction in chicken embryonic livers, the relative biological potency Of HCDD was determined to be approximately 1/4.5 when the potency of TCDD was 1, while OCDD was shown to be inactive. Another type of study which was used to evaluate relative toxicological potency was acute oral toxicity. The following table is a compilation of acute oral LD5QS in the guinea-pig for those congeners that have been studied (from 3. Huff and co-workers, Enviro. Heal. Perspec.. 36:221-240, 1980). �-3- Single Oral LD$Q (ug/kg b.w.) Congener 2,3,7,8-TCDO 1,2,3,4,7,8-HCDD 1,2,3,6,7,8-HCDD 1,2,3,7,8,9-HCDD 1,2,3,4,6,7,8-HpCDD Guinea-pig 2 73 70-100 60-100 > 600 Acute oral toxicity of dioxin congeners has been studied in other species, however, the guinea-pig is being used in this analysis because on an acute basis it is the most sensitive species. An examination of these values reveals that the acute oral LDjns for the three HCDD isomers are very similar. To compare the acute toxicity of HCDD to that of TCDD the lowest reported value of 60 ug/kg b.w. will be used. As in the previous derivation of relative potency, if TCDD is given a value of 1, it follows that the relative potency of HCDD is 1/30 (60 ug/kg-HCDD/2 ug/kg-TCDD) of that of TCDD. Relative potencies for HpCDD and OCDD could not be calculated, because the acute LD$Q for HpCDD was not specifically identified ( > 600 ug/kg b.w.) and no value for OCDD has been reported. A number of reproductive/teratogenic studies have been performed with TCDD, HCDD and OCDD, while none have been reported for HpCDD. In these studies the lowest no observed effect level (NOEL) for TCDD was shown to be at a dosage of 0.001 ug TCDD/kg b.w./day (3-year rat reproduction study; F. Murray and co-workers, Tox. Appl. Pharm., 50:241-252, 1979). In a teratology study by B. Schwetz et al. (Enviro. Health Perspec.. 5_: 87-99, 1973) the lowest dosage shown not to effect embryonal or fetal development for HCDD was 0.1 ug/kg b.w./day. In this same study OCDD did produce embryotoxicity (subcutaneous edema), but no teratogenic effects at 500 mg/kg b.w./day, however, the next lowest dosage, 100 mg/kg b.w./day, did not cause either teratogenic or embryotoxic effects. In comparing the NOELs for these dioxins a relative potency of 1 is assigned to TCDD. It follows that the relative potency of HCDD is 1/100 and that of OCDD is 1/1 X 108 in terms of reproductive toxicity/teratogenicity. Only one of the congeners of interest, namely HCDD, has been studied in a long-term carcinogenic bioassay (NCI, Technical Report Series No. 198, NTP No. 80-12, 1980). In this study a mixture of two isomers, 1,2,3,6,7,8- and 1,2,3,7,8,9-HCDD, was shown to exhibit a lowest effect level (uEL) for neoplasia in B6C3F1 mice of 0.2 ug/kg b.w./day. This compares to the LEL of 0.01 ug/kg b.w./day which was observed by Kociba and co-workers (Tox. Appl. PhaTm., _46:279-303, 1978), in a two-year chronic study in rats. The relative ootency for neoplasia of HCDD in comparison to TCDD would, �-4- therefore, be 1/20. It must be emphasized that in this instance the toxic end-point of neoplasia was used solely to derive a relative potency factor for HCDD, not to address the issue of carcinogenicity, per se. The following table contains a summary of the relative potencies determined for HCDD, HpCDD and OCDD by the methods discussed above. Relative Biological/Toxicological Potencies* Dioxin Conqenar AHH Induction Chicken Liver Rat Embryo Hepatomas 1 1 1/4.5 1/10 HpCDD NR 1/200 OCDD NA 1/25,000 Acute Oral LDsn TCDD HCDD ' Reproductive/ Teratogenic Carcinogenic Bioassay Studies 1 1 1 1/100 1/20 NR NR NR NR 1/1 X 108 NR 1/30 * - 1 is the highest level of activity. NR - not reported; studies have not been performed. NA - not active It is apparent that of the three congeners of interest HCDD demonstrates the greatest activity with HpCDD and OCDD following in order of magnitude. This follows the structure activity relationship for this class of compounds which indicates that those congeners with chlorines in positions 2,3,7 and 8 and with at least one unoccupied ring position will demonstrate the greatest biological/toxicological activity. Derivation of LQCs HCDD The relative potencies of HCDO derived from the various studies cited above range between 1/4.5 and 1/100. Since the incident in question involves an acute or short-term exposure the risk of a pulse (single) exposure during pregnancy would be of most concern. Therefore, while not ignoring the trend suggested by the smaller relative potency factors for HCOD, more weight is given to the larger factor determined on the basis of the teratogenic study performed with HCDD. It was, therefore, decided that a more appropriate relative potency for HCDD is 50. This was then used to derive the LOG for HCDD according to the following calculation - �25 ppt* X 50 X (36.8 g/53.9 g)** = 853 ppt (rounded to 850 ppt) *-• The 25 ppt used in this calculation is the health advisory level which was issued for the TCDD contamination of fish from the Great Lakes. As it was stated previously it is the Great Lakes health advisory which is used as the basis for the derivation of the levels of concern for the higher chlorinated dioxins in the present assessment. **- ratio of food factors; 36.8 g/day - 99th percentile intake for fish; 53.9 g/day - total intake for eggs (28.5 g) and chicken (25.4 g) consumed by children 2 to 5 years of age (supplied by Dr. F. Cordle, HFF-108, 4/14/83, see attachment #3). This level of' 850 ppt, however, applies to the adult and not to children. The latter are of greater concern in this case because they are likely to consume more eggs and chicken per kg of body weight than adult. Therefore, the 850 ppt level is divided by a factor of 3 to account for this increased exposure of children to give a value of 283 ppt which is rounded off to give a LOG of 300 ppt for HCDD. HpCDD The amount of data available on HpCDD is quite meager. If the relative potency value of 1/200 is used, a LOG is derived which is unduly high, particularly in light of the information on the structure-activity relationship of the dioxins. The two hepta isomers have chlorine atoms at carbon positions 2,3,7, and 8, one unoccupied carbon position, and only differ from the most toxic hexa-isomers by the presence of one additional chlorine atom. Therefore, it is felt that a LOG of 500 ppt would be more appropriate. XDD After evaluating the available information on the toxicological and/or biological potency of XDO it was determined that the most reliable data was that from the reproductive/teratology study reported by Schwetz e_t al. (1973). In that study the NOEL for OCDD was 100 mg/kg b.w./day Using this value together with a 1000 fold safety factor and accounting for the lower body weight of 2 to 5 year old child, a tentative LOG of concern equivalent to 30 ppm was determined, as shown below: ' LOG = a « a 100 mg/kg b.w./day (NOEL) $ 1000 (S.F.) 0.1 mg/kg b.w./day x 16 kg b.w. (child) 1.6 mg/day f 53.9 g/day (total consumption of chicken and eggs by child) 29.68 ppm or 30 ppm Wh:!le the value is based on "in vivo" experimentation, it appears to be unrealistically high for a congener which belongs to a class of toxicants, e.g., dioxins, for which so much concern has been expressed. Furthermore, it should be stressed that this value is derived from a single study using �-6- only one animal species, e.g., the rat. If we consider the-"in vitro" data on AHH enzyme induction, it is seen that OCDD has only a minute fraction of the activity reported for TCDD. Nevertheless, there is some concern over the possibility that exposure to OCDD at the level suggested by the tentative LOG of 30 pprn may result in some degree of enzyme induction activity in humans. Therefore, the application of a further safety factor of at least 10 is considered appropriate. Thus, a LOG of 3 ppm is recommended for OCDD in chicken and eggs. Since the amounts of chicken and eggs consumed are similar, a uniform LOG for the respective congeners can be applied to each food item. Again it must be emphasized that these levels apply only to the present situation in Texas and have rio application to other incidents. It should also be reiterated that while the induction of neoplasia was used to derive one of the comparative relative potency factors for HCDD the issue of carcinogenicity was not utilized directly in this evaluation because of the limited, short-term exposure of this situation. Finally, although structure-activity information was considered in deriving the LQCs for the higher chlorinated dioxins it is recognized that additional data on such relationships is required to refine the significance of such parameters in the toxicoldgical assessments of these toxicants. ichael Bolgef, Ph.D. Garfield N. Biddle, Ph.D. Attachments cc: HFF-100 HFF-150 (Blumenthal) HFF-152 (Jackson/Edwards) HFF-159 (Shibko) HFF-159:GNBiddle:MBolger:clw:4/29/83:472-5706:2095A �15. 83--261-360 m PROCESS 12 SUBS - SCRAPINGS FROM EQUIPMENT lb. 33-292-061 1 SUB - SHEEP WOOL FROM SHEEP HEAL SCREEN RECEIVED FROM H.T.C. RENDERING, SAN ANGELO, TEXAS j?. 83-261-062 1 SUB - «EAJ S BONE HEAL SHEEP HEAL 18, 83-292-063 1 SJ!J - POULTRY MEAL !•>. S3- 292- 064 1 SUB - POULTRY HEAL 20. 83-232-065 1 SUB - MEAT 1 BONE MEAL *Ji. 33-292-066 1 SUB - POULTRY HEAL i2. 82-292-067 1 SUB - HEA1 1 BONE HEAL L'li. 83-292-068 J SUB - MEAT I BONE HEAL :'. 33-2^2-069 ;. 1 SUB - UlftTf DEBRI5» ffcOH IKS7PE HEARTH OF OLD 1NCENERATOR •:.Mirriii 10 ciNCiMMAii LABORATORY: 23 SUBS - LUBRICANTS, DEORORANTS, INSECTICIDES. BOILER COMPOUNDS, VARIOUS LIQUIDS ANO POUtERS. UPON RECEIPT OF C/R'S, I WILL DESCRIBE SUBS THAT RELATE TO EACH SAMPLE. i.M RICAKDS TO 83-261-350, SUB 41 HEAT t bONE MEAL* SUB 42 ANIHAL FAT, COLLECTED 5ROH LOAPS RECEIVED FROM TEXAS 6Y PRODUCTS COMPANY, SAN ANTONlD. IT miEVElr TKAt B0TK COMPANIES #RF UNUER THE SftKE 0«NE«T, 1K1S: «2tt & 4/11/83. AS TO COMMON SUPPLIERS, PROCESSING, ETC. �<'«JTL THAI 83-261-350. COLLECTED ON 4/4/83 WAS RECEIVED FROM TEXAS BY-PRODUCTS mnt-ANY, SAN ANTONIO, TEXAS. SUB *1 HF.AT 1 BONE HEAL WAS COLLECTED FROM THE TRANSPORT TRUCK, AND ANALYSIS REVEALED 25.!> PPK. OUR SAMPLE 83-260-356. MEAT i BONE MEAL. COLLECTED 0« 3/H/B3 REVEALED 16.0 ?pH TCP'S. THIS SAMPLE WAS COLLECTED FROM A STORAGE BIN, AND IS NOW BELIEVED TO BE A PORTION RECEIVE* n»DH TEXAS BIT-PRODUCTS. TEXAS WNUER1N6 IS OWNED BY HUBEW L. L1NENBERQER, AND ALSO FUNCTIONS AS THE PRESIDENT. LINENBER6ER ALSO OWNS 75* OF THE STOCK OF TEXAS BY-PRODUCTS, SAN '.rtlOMlO, AS WELL AS OWNING A hAJOR INTEREST 1M TEX -HENS, INC., MIXON, TEXAS. TE/.AS kENliERlNG RECEIVED APPROX. 3-4 LOADS OF HEAT I BONE iiEAL PEft WEEK FROM TrxAS BY-PRODUCTS, ESTIMATED AT APPROX. 150,000 LBS. OK MORE. IT WAS REPORTED THnT THIS HEAT 1 BONE HEAL IS VERY HIGH IN FAt CONTENT AND IS RUN THROUGH THE EQUIPMENT AT TEXAS RENDERING TO EXTRACT ADDITIONAL FAT, IT IS ALSO REPORTED THAT PRODUCT SAMPLED UNDER 03-261-350, SUB 12, ANIMAL FAT FROM TEXAS ST-PRODUC7S IS ACTUALLY STREET GREASE. Ml IS NOT ANIMAL FAT PROCESSED BY ANTONIO. REPORTEDLY DOES TO JACOB-SIERNS, HOUSTON, TEXAS. WHILE TEXAS PJNDER2WJ RECEI'/ES KEAT I PONE HEAL AND STREET GREASE- FROK TEXAS BY-PRODUCTS, SAN ANTONIO, TEXAS RENDERIMf, JOES NOT SHIJ1 PRODUCTS TO THEM. ALSO IT WAS REPORTED, THESE FIRMS DO NOT HAVE COMMON SUPPLIERS. ALSO NO PRODUCTS ARE SHIPPED PROM TEXAS RENDERING TO TEX-HENS, INC., NIXON, TEXAS. (. GENERAL PROCESSING FLOW AT TEXAS RENDERING IS AS FOLLOWS: AS PRODUCT IS RECEIVED, HEAT X BONE MEAL, DEAD ANIMALS, SCRAPS, ETC., IT IS ^JftPED JKTO A P3T WHERE 37 IS AUGCRED TO 70 AH 3NI>US?kiAL 6K3MER, AUGERS OVER rAGMETIC PLATE (REMOVE HE? AD TO MEAT STORAGE VAT, 10 QHE OF 5 HEAT COOKERS. THE COOKERS ARE CHARGED WITH APPROX. 6,000 L*S. OF PRODUCT AND APPKOX. 2,000 LK-. OF ANIMAL FAT- JS ADBE& (USUALLY PROCESSED THE rtiGHT BE?OR£>. AFTER COOKING AT APPROX, 313 DEGREES t. THE PRODUCT EXITS AND SCREENED WITH THE FAT V.CIM13 TO ONE OF 3/20,000 LB. WORKING VATS. THE FAT IN THESE VAIS IS USED TO INTO THE COOKING VATS AS STATED ABOVE. IS NKXBCD FROM THESE WORKING VATS. IT MAINS TO A FLAT DRYING VAT TO »>r off WATER. FROM HERE, XT. is PUMPED TO EITHER OF 3/30,000 LF\ STORAGE VATS. ^r. THE MEAT EXITS THE COOKER, IT GOES TO THE PRESSES «HESE BORE FAT IS UTKACTED (PAT GOES TO THE WORKING VATS). THE MEAT THEN PASSES THE SCfcEENEJc, .MJBCIXI kA»a« ftiaeso A* »««4S, MAIM, »*o.t >H».» M«MOV»». *M» HBis* *t*0*4 ««aa *o T'riE HAMMER t»U. THEM THE MEAt T& EITHER OF 8/60,000 t&3. STORAGE BINS AS iTMISHED MEAL. THE BONES, ETC., REMOVED BY THE SCREENER, GOES BACK TO THE L'KJSINAL AUGER AT THE STARTING POINT OF THE PROCESS. L'JSCUSSIONS WERE HELD OK MONDAY. 4/U/83, BY HOUSTON STATION WITH OFFICIALS Of TrlC TEXAS KEPT. OF AGRICULTURE AND TEXAS DEPT. OF HEALTH AND OUR SAMPLE ilTSULIS KNOWN AT THE PRESENT TIME WERE PISUCSSED. THE INTRASTATE SHELL EG^S «t*£ DISCUSSED WITH TEXAS DEPT. OF HEALTH, HOWEVER, THEY DO MOT HAVE THE :«*AmniES OF ANALYSING FOR POP'S 10- DETESHINEiTHS CU»*EM STAJUS- or EGGSC t A "P:0n SMITH FARMS AMD POSSIBLY OTHERS. !PJ^ **<WHifc- CU5RENT ASSAYS. THEY \Ki «ILL1HG TO ACT., HOWEVER ^REQUESTED THAT FDA PRO'/lIiE GUIDANCE AS TO HEALTH '•¥" REGULATORY SICNifANCE AS WELL AS ACTION GUIDANCE. �nr xcxft* DEFT. OF AGRICULTURE IS QUITE CONCERNED AND 15 CURRENTLY lVG SAMPLES SUBMITTED BY 1KB F1RH OF FINISHED PROBUCT, HO«BVBR> THEY •ilSO R£QU£S7£H TKun THE HIGH LEVELS Of ?C?'& FOU*fB IW «EAI I BOME HEAL FUtOM TEXAS Pr-PRQPUClS, SAN ANTOfilO, IT A?f-EARS THAT THIS COULD BE A CONTINUOUS SOURCE OF LOfJTAMiNATEB PRODUCTS. AN INVESTIGATION OF THIS FIKH IS CURRENTLY BEING. UISUUSSED. �/'*• REGULATORY TOXICOLOGY AND PHARMACOLOGY 1, 379-387 (1981) The Use of Epidemiology in the Regulation of Dioxins in the Food Supply1 FRANK CORDLE Epidemiology and Clinical Toxicology, Bureau of Foods, food and Drug Administration, Washington, D. C. 20204 Received November 1981 Residues of teirachlorodibenzo-p-dioxins (TCDD) were detected recently in several species of freshwater fish from various areas of the Great Lakes. Concern for the potential human health risk associated with the consumption of these fish prompted the Food and Drug Administration to assess epidemiological and toxicologies! TCDD data in order to determine the need for regulatory action. In the assessment, pertinent animal and human data and daia for the TCDD residues in the freshwater fish, for the amounts of the different fish species consumed and for the number of individuals who consumed the fish, were evaluated. The various methods of evaluation used to reach a regulatory decision are described. * INTRODUCTION Although epidemiology may have first been used by Hippocrates, the definition or meaning has undergone some significant changes since then. First described as the study of epidemics and, later, as the study of the determinants of differences in disease distributions in human populations, epidemiology today, especially in regulatory agencies, refers essentially to the activities of the epidemiologist. In a regulatory agency such as the Food and Drug Administration (FDA) the role of the epidemiologist is to assimilate, digest, and synthesize the best available data from survey, clinical, and laboratory experiences, either firsthand or from the scientific literature: these human and animal data are then combined and interpreted in order to address a basic question: Does the evidence of adverse human health effects from exposure to the various chemical substances that fall under FDA regulatory authority present a risk to public health safety that is sufficient for FDA to initiate or make a change in regulatory action? The importance of the contri• Presented at the international symposium Human Health Aspects io Accidental Chemical Exposure of Dicxir.s—S::aisgy for Environmental Reclamation snc Corr.mur.itv Protection, organized by the International Academy of Environmental Safety (1AES) and the International Society of Ecotoxicolojy and Er.viro.-.rncnta! Safety (SECOTOX) joiniiy with the Institute Superiore di Sanita. Rome, and the Geseilschafrfur Strahien- und Umweh Forshung MbH, Munich. 379 o::?-::-oo;si/o:>o379-o9so:.oo/o Cc??Ti9i: 5 19M tv Academic Presi. Int .Mi nf hu of rep.'odumor. in >nv form reserved �380 FRANK CORDLE bution of epidemiology in the regulatory public health arena seems obvious. Without adequate assessment of factors that appear"to increase the risk of disease in humans from chemical substances in the food supply, food may be destroyed, the public may be unnecessarily inconvenienced or inadequately protected, and the costs may be enormous. In short, epidemiological efforts are directed toward the prediction of such risk at the community, state, or national level. It is quite likely that the majority of humans are exposed to a large number of chemical substances in small amounts over an extended period of time rather than to large doses such as those described in the mercury episode in Minamata or in the PCB exposure in Japan. The importance of the possible cumulative effects from these small doses versus the importance of the effects from a single large dose or .from relatively large doses over a short period of time is the subject of considerable scientific debate. Much of the information concerning the toxicity of various chemical substances has been obtained from experiments in animals. In general, safety testing depends upon the fact that as the exposure dose is decreased, toxic effects also decrease, and a dose is finally established at which "no observed effects" are seen. Such dose-response relations are central to toxicity studies in animals and should be ef equal concern in the evaluation of human exposure to a variety of environmental and other insults. However, dose-response relations in humans must be established or identified with a great deal of care and caution. Outcome may vary greatly in significance: At one extreme is death and at the other are changes in physiological or psychological function. The weight that should be given to each relation in formulating regulatory policy may vary greatly. The lack of good examples of dose-response 'relation, even in the area of occupational exposure, is remarkable. Where dramatic incidents of exposure to environmental contamination have occurred through ingestion of contaminated food, efforts to establish an acceptable dose-response relation in humans have met with little success. However, epidemiologies! study should not be limited to outbreaks of disease that are obviously caused by high exposures to toxic chemicals: it should be squally concerned with the effects of lower, more prolonged, and sometimes insidious exposures. EPIDEMIOLOGICAL METHODS In the traditional manner, epidemiologists deal wi;h epidemics by interpreting patterns of disease, testing hypotheses, and assessing the risks and benefits of various options. Their methods involve the use of two categories of epidemiology often referred to. as analytical and descriptive epidemiology. The analytical epidemiclogical methods generally involve either a case-control, retrospective approach or a cohort, prospective approach. In analytical epidemiology, the goal of epicsmioiogica! activity is to identify and. if possible, to quantify the association between a cuusii exposure or characteristic and a disease under circumstances that permit the best possible discrimination between cause and aiternative hypotheses. Chance will always affect the alternatives: thus the feasibility of such a study is limited by factors such as sample size. �EPIDEMIOLOGY AND REGULATION'OF D1OXINS -" 381 Since a precise hypothesis permits the use of a well-thought-out and properly planned study design, it is better to use the cohort approach to measure relative and attributable risk, for example, than to try to detect trends from descriptive data. Nevertheless, sample size considerations, cost, and time constraints often restrict the kind of epidemiological study undertaken, even though the cohort approach might be preferred for a given problem. Case-control studies of disease, i.e., studies looking at the past history of exposure, are often more feasible than cohort studies because they can be conducted in a relatively short time and are easily repeatable, and because a large number of cases can be studied economically. They do have some special liabilities, however, in terms of validity, since such studies depend entirely on the comparability of cases and controls and on the specific methods used to measure the exposure. Although frequently used, the methods for estimating relative risk or risk ratio from casecontrol studies also present some special problems of inference. Cohort studies, i.e..-studies looking forward in time, are especially costly because of the time involved in the prospective follow-up. They do, however, provide an opportunity to compute a more reasonable relati%re and attributable risk, and specious relationships resulting from bias in data collection are less likely to occur. Descriptive epidemioiogical methods can be used by a regulatory agency such as FDA to determine trends in disease and magnitudes of exposed populations largely from data that are readily available, e.g., mortality dau. data from National Cancer Institute (NCI) surveys, census data, and food consumption data. The goal of these studies is io identify any unexpected changes in incidents or.mortality through surveillance of the available data for time trends and through probes of specific data collected during research activities or gathered in support of regulatory decisions. Epidemiological studies also provide information that is used to identify and quantify differences in species responsiveness to environmental agents in a variety of other ways. One use. for example, pertains to the difficulty associated with cornparir.c data derived from studies of highly inbred animal strains to data of a genetically heterogeneous human population. In this case, epidemiological methodologies provide the means for stratification of study data according to sex, age, race, and other variables that characterize human populations. Certain problems rr.ay also be minimized when epiderniological considerations are employed in risk assessments that are based on comparisons involving data of humans and data of animal models. These include problems associated with limited sample sizes, znigra'.ior. in and out of the exposure area, and toxicity due to causes other than that as-sociated Vjth exposure to the etioiogic agent under study. EPIDEMIOLOGICAL AND TOXICOLOGICAL ASSESSMENT OF TCDD EXPOSURE Recent concern for the potential human health risk associated with exposure to residues of the tetrachiorocibenzo-p-dioxins (TCDD) in several species of freshwater fish from various areas of the Greai Lakes has resulted in an epidemioiogical arc toxicological assessment of the problem that utilizes currently available data from a variety of data sets. For a regulatory decision to be made, several elements �3S2 FRANK CORDLE were needed. These included data for the TCDD residues in the freshwater fish, for the amounts of the various fish species consumed and for the number of individuals who consumed the fish, and assessments of pertinent animal data and previous human exposure to TCDD. Animal Data A number of lexicological studies with TCDD have been conducted to assess the potential for acute toxicity and teratogenesis. Kociba et al. (1976) reported the results of a subchronic study using rats that were given 1.0, 0.1, 0.01, 0.001, or 0 /jg TCDD/kg body wt/day for 5 days/week for 13 weeks. Doses of 1.0 Mg TCDD/ kg/day caused some mortality, inactivity, decreased body weights and food consumption, pathornorphologic changes in the liver, lymphoid depletion of the thymus, increased urinary excretion of porphyrins, and minimal alterations of some hematopoietic components. Doses of 0.1 ^g TCDD/kg/day caused decreased body weights and food consumption and slight degrees of liver degeneration and lymphoid depletion. These data indicate that no discernible ill effects occurred in rats given 0.01 or 0.001 jig TCDD/kg/day for 5 days/week for 13 weeks. In a 2-year chronic study in rats Kociba et al. (1978) reported that the ingestion of 0.1 ,ug TCDD/kg/day caused an increased incidence of hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue, whereas a reduced incidence of tumors of the pituitary, uterus, mammary glands, pancreas, and adrenal glands was noted. Other indications of toxicity at this dose level included increased mortality, decreased weight gain, slight depression of erythroid parameters, and increased urinary excretion of porphyrins. Gross and histopathologic charges were noted in the hepatic lymphoid. respiratory, and vascular '.issues. The primary hepatic ultrastructural change at this high dose level was proliferation of the rough endopiasmic reticulum. Terminal liver and fat samples from rats given this high dose level contained 24.000 and S100 parts per trillion (ppt) TCDD, respectively. Rats giver. 0.01 ng TCDD/kg/day for 2 years showed less severe toxicological effects than those given the highest dose level. These included liver lesions (including hepstocellular nodules) and lung lesions (including focal alveolar hyperplasia). Terminal liver and fat samples from rats given this dose level contained 5100 and 1700 ppt TCDD, respectively. Ingestion of 0.001 yg TCDD/kg/day (22 ppt in the die;) caused no effects of any toxicological significance. Terminal liver and fat samples from rats given this low dose level each confined 5-^0 ppt TCDD. ]- a 3-year reproduction study in rais given doss levels of 0. O.OOL 0.01, or 0.1 ug TCDD/'kg/day, Murray ei al. 'J979) reported no significant toxic effects in the/c-ceneration rats of cither se.x curing the 90 days of TCDD ingestion prior to ': mating. However; significant decreases in fertility and neonatal survival were observed in the/o-generation rats receiving 0.1 ps TCDD/kg/day. At 0.01 Mg TCDD/ kg/day, fertility was significantly decreased in the/i and/ : generations, but not in the/; generation, and decre55.es in litter size at birth, gestations! survival, and neonatal survival and growth were also noted. Among the rats receiving 0.001 ^g TCDD/kg/day, no effect on fertility. !i;:er <ize at birth, or postnatal body weight was observed in any generation. No consistent effect on neonatal survival was observed at a dose level of 0.001 pg TCDD/kg/day. • �EPIDEMIOLOGY AND REGULATION OF DIOXINS 383 Allen et al. (1977) reported results of a subchronic study in which female rhesus monkeys consumed a diet containing 500 ppt TCDD for periods as long as 9 months. It was calculated that these monkeys ingested a total of 2-3 Mg TCDD/kg body wt over the course of the 9-month study. Clinically, these monkeys showed changes similar to those described by McConnell et al. (1978) as well as some hematoiogic depression and hemorrhages in various tissues. Hypertrophy, hyperplasia, and/or metaplasia were noted in the epithelium of the bile ducts, salivary glands, bronchi, pancreatic ducts, sebaceous glands, skin, gastric linings, and urinary tracts of these monkeys given diets containing 500 ppt TCDD. Human Experience Alihough 22 incidents of human exposure to TCDD in connection with the manufacture of chlorinated phenols have been reported worldwide since 1949 (Holmstedt, 1980). there remains a scarcity of reliable information concerning the results of these exposures. In a recent report of the mortality experience of a cohort of workers exposed to TCDD in Nitro, West Virginia, in 1949. Zack and Suskind (1980) described some of the signs and symptoms observed in the exposed population shortly, after the accident occurred. Employees who-worked in the area of 2,4.5-trichlorophinol (TCP) production or were involved in the cleanup began to develop symptoms immediately following exposure to the material, which was discharged froir. the autoclave. Symptoms included eye and respiratory tract irritation, headache, dizziness and nausea, and a severe irritant reaction of the exposed skin. After these initial symptoms subsided, chioracne and other symptoms became evident. A total of 12 more severely affected workers were examined or. three occasions during the period 1949-1953. Another 26 persons with chioracne :hat was apparently unrelated to the accident were also examined in 1953. The ciinical symptoms included acneform lesions: severe pains in muscles of upper and lower extremities, shoulders, and thorax on exertion: fatigue: nervousness and irritability: decrease in libido: dyspnea: vertigo: and intolerance to cole. All of the cases showed evidence of chioracne. For the six workers examined curing 1949 and 1950. another examination was carried out in 1953. and at that time six additional workers involved in the accident were also examined! The findings in ihis later examination indicated a general regression of both the cutaneous and ne.-cuiijriccus symptoms w h i c h had been present earlier. No specific leveis o; exposure could be determined. In other reports of industrial exposure 10 TCDD frc.T. Great Britain, the Netherlands. \\fisi Germany, and Czechoslovakia, chioracne was the most common and prominent sign observed following exposure. In some -sports liver function tests indicated liver damage, whereas in other reports they die not. Two major problems er.cour,:e:tc in all of these studies were the lack of 2. tltitr identification of •.hose e.v-<>=d. other than their subsequent development of chioracne. and the absence of any measures for the levels of exposure ihar might have taken place. Pszdsrova-Vejlupkova et a!. ( 1 9 8 1 ) reported results of a 10-year follow-up study of workers exposed ;o TCDD between 1965 snd 196s curing the production of 2.4.5-trichloropheno.xyacetic acid (2/,5-T). In this s t u d y group of 55 individuals �384 FRANK CORDLE (originally 80 of the 400 persons engaged in., the production became ill), the first indications of illness were feelings of sickness, fatigue, weakness in the lower extremities, and the formation of chloracne. Subsequent examinations indicated that about 20% had mild hepatic lesions. During the 10-year follow-up study of these exposed individuals, most of the patients did not experience all of the symptoms and signs of intoxication, and some patients showed the same symptoms and signs as others, but in different combinations. It is assumed that in this type of intoxication all the systems and organs mentioned in the study were simultaneously affected, although some were affected only slightly. This assumption is supported by several facts. Fluorescence of liver tissues in ultraviolet light, which is a sign of pathological porphyrin metabolism, was present in all cases of necropsy and biopsy, i.e., in persons for whom long-term monitoring of porphyrin excretion in urine was carried out and in whom 5-aminolevulinic acid values were constantly within normal limits'. Probably a slight subclinical lesion was present in each of these patients. Further evidence was furnished in repeated neurological examinations. Polyneuropathy of the lower extremities was manifest in some patients only in the third or fourth year of illness. There is definite clinical and electromyographic evidence that the results of the first examinations conducted when the illness commenced showed that the patients were entirely normal. Additional study results have been reported recently by Zack and Suskind 0980), Ott et al. (1980), and Cook et al. (1980), describing ;hs mortality of employees engaged in the manufacture of 2.4.5,-T. In two of these studies cohorts of employees were assembled on the basis of their exposure to T.CDD. which was indicated,by the presence of chloracne; the ihird cohort consisted of individuals employed over the same time period. Unfortunately, each of these three cohorts comprised a limited number of individuals: e.g., the chloracne groups contained 121 and 49 individuals and the employee group contained 204. In each of these studies there does not appear to be an apparent excess in total mortality rate or in deaths from malignant neoplasms. It must be pointed out, however, that each of these studies does have limitations both in the size of the population studied and in other methodological areas, such as exposure levels. For a more detailed description of these studies as well as the Seveso incident, the reader is referred to the original papers and to Hoimstect (1980), Reggiani (19SO), and Pocchiari et al. (1979). Hitman Exposure to TCDD Residues in Fish Although there are no epidemiological studies which have firmly established an association between cancer in humans and TCDD exposure, 2nd although comparisons of human exposure data and animal studies appear to indicate that humans may be less sensitive than animals to TCDD exposure, prudence dictates that human exposure to TCDD be kept to 3 minimum. With :h:s public health objective ir. m;rd. FDA recently compieted an assessment of the problem of TCDD residues in some species of freshwater fish in the Great Lakes for ;he purpose of determining whether consumption of such fish provided a potential public health problem. Results of the analyses of fish samples collected by Canada and the United States �EPIDEMIOLOGY AND REGULATION OF D10XINS - 385 TABLE i HUMAN CONSUMPTION OF DIOXIN BASED ON FISH CONSUMPTION DATA Total daily intake (ng*) Total daily intake/body wt (pg'/kg) From all selected species From all selected species Hypothetical dioxin residue level in fish consumed (ppf) 90th percentile 99th percentile From pike, 99th percentile 90th percentile 99th percentile From pike, 99th percentile 100 SO 25 1.57 0.77 0.38 3.683 1.84 0.92 8.4 4.2 2.1 22 11 5.5 50 26 13 120 60 30 ' ppt • pans per trillion. " 1 microgram (»g) "..1000 nanograms (ng). ' 1 ng - 1000 picograms (pg). indicated that TCDD levels as high as 30 ppt with an average value of 25 ppt were present in the edible portion of salmonoid fish (salmon, trout) from. Lake Ontario. Lower levels of TCDD were reported to be present in the edible portions of commercial species (bullhead, perch, catfish, sucker, etc.) from Lake Ontario^ although up to 40 ppt TCDD were found in'eel and smelt from the lake. Less than 10 ppt TCDD was seen in samples from Lake Erie, and limited data for_fish from the other Great Lakes were similar to those obtained from Lake Erie fish, except that higher levels of TCDD were present .in fish from Sagir.aw Bay, Michigan. Data on fish consumption from the National Marine Fisheries Service (NMFS) were extracted for the eight Great Lakes states, Illinois. Indiana. Michigan, Minnesota. New York, Ohio, Pennsylvania, and Wisconsin. These data were collected in a national sample of households, consisting of approximately 25,000 individuals. From the data presented, individuals who consumed the species of interest, i.e., the species currently being analyzed for dioxin residues were identified in the total sample, and the mean fish consumption, in grams per cay. was computed. The 90th and 99th percentiles were also computed. On the basis of the proportion of individuals in the sample population consuming the species of interest, 17,057,791 individuals in the eight Great Lakes states would be expected to consume these same species. It must be pointed out that the number of consumers in the total population can be considered only ar. estimate because of the lack of information on potential sampling error as well as other factors. These data indicated that the 99th percentile for daily consumption for all consumers of the selected species was 36.8 g; the 90th percentile for daily consumption was 15.7 g. For a single species of fish such as pike, which appeared to be consumed in larger amounts than all the species combined, the 99th percentile of consumption was 83.95 g. Table 1, which is based on these fish consumption data, shows :he daily human consumption for a range of hypothetical dioxin residue levels. Thus, the four elements of the model for a scisn::f.c regulatory assessment, i.e., animal data, human data, consumption data, and residue data, were available. In this instance the h u m a n data concerning TCDD exposure contributed little to the regulatory decision because of the uncertainty of the exposure data as well as the �386 FRANK CORDLE uncertainty of the outcome of the exposure. It was necessary, therefore, to rely on extrapolation from animal to human. In this case the rodent data from the 2-year chronic feeding study (Kociba ei a/., 1978) were used for the extrapolation. Results of that study showed that (a) at 0.001 Mg/kg body wt/day, no adverse effects were noted in rats exposed for their lifetimes to the dioxin; (b) at 0.01 ng/kg body wt/day, hyperplasia of the liver and lung was observed to occur, thus indicating an observable effect related to enzyme induction and liver cell response to the compound; (c) at 0.1 Mg/kg body wt/day, an increase in liver carcinomas was observed. The animal-to-human extrapolation of the no-effect level for TCDD exposure from the rodent data indicated an intake of 1 ng/'kg body wt/dav or a total daily intake of 70 ng as the no-effect level. If fish containing average TCDD residue levels of 25 ppt were consumed in the amount of the 99th percentile. i.e., 36.8 g/' day. the total daily intake of TCDD would be 0.92 ng or 13 pg/kg body wt/day or less than l/70th of the no-effect level, less than 1/700th of the lowest-effect level, and less than 1 /7000th of the carcinogenic level. The safety margin at the 90th percentile of consumption is even greater. As a result of this assessment, a public health advisory was sent to the health v officers in each of the Great Lakes states, encouraging a continued mor.itoring of TCDD residues in fish, especially in certain local areas where TCDD levels mightbe higher than the average, and where Local fish consumption might also be higher than that for the Great Lakes area as a whole. This exa.r.ple in regulatory decision making illustrates FDA's role in protecting public health by ensuring a safe and nutritious food'supply. This responsibility is exercised by individuals who call upon science, law, and the regulatory process to accommodate the demands of safety, contamination, food requirements, Congress, consumers, and the courts. Although the regulatory process has often been criticized, on the whole it has provided effective public health protection for the millions who consume food in the United States. REFERENCES ALLEN. J. R.. BARSOTT;. D. A.. VAN MILLER, J. P., ABRAHAMSOS. L. L. AND LAUGH. J. J. 09"). Mcrp'-oiogica! changes in monkeys consuming a diet co.-.;aining low isvsis of ;.3.~.S-tei:ichlorodiber.io-p-c'ioxin. Food Cosmct. Toxicol. IS, 401-410. COOK. R. R.. TOWNSEND. J. C. OTT. M. G.. AND SILVERSTEIN. L. B. (!9SO). Mor.a!h> experience . cf srspic.yeej exposed to :.j.T.S-ieirachioro<Jib«.-i20-..--cio.\ir.. JO.'.f J. 0^-ap. .'•'<::. 21. <3C-<21 HOLMSTSCT. B. 119SO). Prolegomena to Scveso. Arch. Toxicoi. 44. :i l-:;-0. KOC:SA. R. J.. KsELER. P. A.. PARK. C. N.. AND GEMMING. P. J. H976). 13.7.&-7j',ri:hic-:ociber.:op-cio.\in (TCDD;: Results of a 13-week orii loxiciiy s;udy in rats. Toxicol. Appl. Phsrn-.acol. 35, 553-574. KOCISA. R. 1. KEYSS, D. G.. SEVER.-J. E.. CARRSON, R. M.. \VADE. C. £.. DITTENJIER, D. A.. KALMNS. R. ?.. FRACSON. L. E., PARK. C. N.. BARNARD. S. D.. HUMMEL, R. A.. AND HCMISTOS. C. G. ('197*1. Results of a two-year chronic :oxic::y and oncng«riici:y jiucy o.f ;.3.7.S-;e::s>ch!oro•iiber.io-p-dicxir. i.-..ra:s. Tbxifol. .*.,-,"!. Pksrmecol. 46. "9-?03, McCosvaiJ.. £. E.. .'MOORE. J. A., AND DALOARO. D. W. (197S). Toxicity of :,3.7.S-ie:;achlorocibcr.^o-/i-cioxin (TCDD) ir. rhesus rnonl.eys (Macaco mvlci;a'i follow, jr.; 2 sir.gie orai dose. Toxieol. Af-p!. Pns.'rr.cto!. 43, 175-187. MUKP.AV. F.. J.. SMITH. F. A., SITSCHKE. K. D., HAMESTON. C. G., KocibA. R. J., AVD SC.HWETZ. �EPIDEMIOLOGY AND REGULATION OF D10XINS 387 B. A. (.1979). Three-generation reproduction study of rats given 2.3,7.8-ietrachlorodibenzo-p-dioxin (TOO! ir. '.he diet. Toxicol. Appl. Pharmacol. 50, 24J-252. Orr. M. G.. HOLDER, B. B., AND OLSON. R. D- (1980). A mortality analysis of employees engaged ir. the manufacture of 2.4,5-trichlorophenoxy acetic acid. JOM J. Occup. Mtd. 22. 47-50. PA2DsROVA-V£JLUTKOv.v J.. NgWCOVA. M., PlCKOVA. J.. JlRASEK. L, AND LUKAS. E. (1981). The oeveiopmem and prognosis of chronic intoxication by t«rachlorodibenzo-/>-dioxin in men. Arch. En\-iror.. Heolih 36, 5-11. PoccHiARi. F., SILANO. V., AND ZAMPIERI. A. (1979). Human health effects from accidental release of tetrachlorodibenzo-p-dioxins (TCDD) a; Seveso. Italy. Ann. N. Y. Acad. Sci. 320, 311-320. RECC:AM, G. U9SO). Acute human exposure to TCDD in Seveso, Italy. / Toxicol. Environ. Health 6, 2?-43. ZACK. J. A.. AND SUSKIND. R. R. (1980). The mortality experience of workers exposed to tetrachiorodibenzodioxin in a trichlorophenol process accident. JOM J. Occup. Med. 22, 11-14. �f. CooiU Ajril H, t ^ S PCOD INTAKE FOR DIOXIN, PCP LEVELS OF OONCESN 18-45yrs 2-5yrs bw.71.2 bw.16.3 total red neat and poultry Ibtal red meat 212g 108g 109.6g Beef 134g 65.6g Veal Beef + veal 20g 136g Lairb + mutton Beef liver 17g 20g Pork Pork (45-64 years) 67g 75g 36^3g 8g 6.7 Pork liver Poultry (total) Poultry (total; 45-64 years) Chicken Chicken (45-64 years) -.• Chicken liver Turkey Duck ' 53g 56g 44g 47g 13g 33g 17g 25.4g 4.4g' Eggs Ecgs( 45-64 years) 47g 58g 28.5g Milk fat Milk fat( 13-17 years) Non-fat railk Ken-fat milk (13-17 years) 24g 31g 48g 74g 23.4g �Samples collected fron Smith Farms (26 operating farms) en 1/17/83 Eggs Eggs Eggs Eggs - Farm £34 - K&M Farm - Farm #40 - Benders Farm 0.20ppm (PCP) O.lSpcm (PC?) O.~13ppm (PCP) Feed Feed Feed 0.26ppn (PC?) Feed O.OSppm (PC? 0.07ppra (PC?) Trace (PCP) . Trace (PCP) Food consumotion bv days and meals: Beef Perk Chicken Eggs Milk fat Other 18-45 years 134g X 5 ireals=670g 75g X 5 neals=375g 44g X 4 meals=176g 47g X 7 msals=329g 24g X 7 iTBals=168g 30g X 7 neals»210g 1928g 1928g/7=275.4g/day 2-5 years 55.6g X 5 meals=328c 36.3g X 5 neals=182g 25.4g X 4 m=alssl02g .28.5g X 7 meals=200g .23.4g X 7 nfials=174g 10.Og X 7 maals-TO^ 1056c 1056g/7=151g/day � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 051 Folder The folder containing the original item. 1353 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Barnes, Donald G. Title A name given to the resource Memorandum: FDA Risk Assessment for Higher Chlorinated Dibenzo-p-dioxins, from Donald G. Barnes to Alvin Young and others, May 13, 1983 Subject The topic of the resource dioxin dietary exposure animal testing ao_seriesIII