Document 06MkN6qNJOBGKbRj11xwNqODR

JUL-i-93 THU 15i 16 WILLIAMS & CONNOLLY -' 1 i ROBEA.T J. 5HAUGHNE55Y (302) 434*5564 LAW GFFIC5 W ILLIAM S 8 C O N N O LLY 725 TWELFTH 5TREET, N.W. WASHINGTON D. C- 20005 C202) 434-5000 , FAX (202)'1434-5029 ,! 'i I i P. 01 I IC W A t BNWETT VILLtAM S (1 0 3 0 -1 8 8 0 ) P A U L 1- ( Q N X g U Y u a a - l B T B ) I TELECOPY TO: FIRM: TELECOPY NUMBER: W M e t c -H ) ! 6ftfta<CR6|Ma>*fifr f s o i iir e ' I !I (7021 3PP8 WO ! 3 8 S '~ / & S S ' FROM: \ i ROBERT SHAUGHNESSY TELEPHONE: 2021 434-5564 DATE: CLIENT CHARGE: G102.084 N U M BER OF PA G ES INCLUDING THIS PA G E 1 I j IF TH ERE A R E AN Y PR O BLEM S RECEIVIN G THIS TRANSM ISSION, PLEA SE CALL (202) 434-5607 IMMEDIATELY. THANK YOU. , THIS FACSIM ILE CONTAINS PRIVILEGED AND CONFIDENTIAL INFORMATION INTENDED ONLY FOR THE U SE OF THE A D D R E S S E E S NAMED ABOVE. YOU ABE HEREBY NOTIFIED THAT ANY DISSEMINATION OR COPYING OF THIS FACSIMILE IS STRICTLY PROHIBITED, IF YOU HAVE RECEIVED TH IS FACSIM ILE IN ERROR, PLEASE NOTIFY U S IMMEDIATELY BY TELEPHONE AND RETURN THE ORIGINAL FACSIM ILE TO US AT THE ABOVE A D D R ESS VIA THE U.S. POSTAL SERVICE. THANK YOU. I W ILLIAMS & CONNOLLY TELECO PY NUMBER:| (202) 434-5029 i b e c e ' vE \ CHEMICAL MANUFACTURERS ASSOCIATION MG 2 8 138! I S . B. HAMU-T August 26, 1986 ii TO: Dibenzofurans/Dibenzodioxins Program Panel FROM: C. Stack -- /{ RE: Recent Filings and Documents For your files the following is enclosed: I * Panel comments on the EPA Health Assessment Document on Dibenzofurans and cover!letters to Drs. Milkerjee and Byrd; : |. | * Panel comments on EPA's[Toxicity Equivalency Factors Scheme and cover letter to Dr. Yosi; ( * The Panel's "Considerations for Assessing Potential Human Risk from Exposures to 2,3,7,8-Tetrachlorod benzodioxin sent to all of above; r * The April 1986 draft of EPA's "interim Procedures for Estimating Risks Associated with Exposures to Mixtures of Chlorinated Dibenzo-p-dioxins and Dibenzofurans (CDDs and DCFs')" *1 g\03l0 783621 I !l Formerly .Manufacturing Chemists Association-- Serving the Chemical Industry Since 1872. 2501 M Street, NW Washington, DC 20037 Telephone 202/887-1100 'Tte* row a uirw y CHEMICAL MANUFACTURERS ASSOCIATION GERALDINE V. COX. Ph.O. Vice President Technical Director August '25, 1986 BY HAND Terry F. Yosie, Director Science Advisory Board, A-101-F Environmental Protection Agency I < 401 M Street, S.W. Washington, D.C. 20460 [ Dear Mr. Yosie: i 1j 1 '' 1 The Dibenzofurans and Dibenzodioxins Panel of the- Chemical Manufacturers Association (CMA) requests the opportunity to make a five-minute presentation at the Science Advisory Board's (SAB'sj) Dioxin Toxic Equivalency Methodology Subcommittee meeting on September 8jj-9, 1986. Dr. James Wilson will make the presentation on behalf of the Panel and will comment on EPA's "Interim Procedures for Estimating Risks Associated with Exposuresj to Mixtures of Chlorinated Dibenzo-p-Dioxins and Dibenzofurans|(CDDs and CDFs), the subject of the SAB Subcommitteejmeeting. We are submitting with this letter a copy of the Panel's written comments on EPA|'s Toxic Equivalency Factor (TEF) Scheme for predicting risks from chlorinated dibenzo dioxins and dibenzofurans. Dr.'Wilson's presentation will briefly summarize these comments. We are also enclosing with;this letter (Attachment I) a copy of a working paper prepared by the CMA Panel entitled "Considerations for Assessing the Potential Human Risk from Exposures to 2,3,7,8-Tetrachlorodibenzodioxin." j EPA's Toxic Equivalency Factor Scheme represents an effort by EPA to develop risk values for a number of chlorodibenzodioxins and chlorodibenzofurans in relationship to the [toxicity of 2,3,7,8-TCDD. It thus is obviously important th!at EPA accu rately and reliably determine that underlying TCDD value. GENP 010811 783622 .I i Formerly Manufacturing Chemists Association-- Serving the Chemical industry Since 1872. 2501 M Street. NW Waahinnton n r *nni* - t- i-- *------- -- - ----- " - I Terry F. Yosie, Director August 25, 1986 Page 2 ' I i The Panel*s working paper discusses the variance between KPA's 1985 risk assessment of TCDD and assessments of other international expert panels. It concludes) that] EPA over estimates the potency of TCDD by approximately three orders of magnitude. Because the underlying TCDD risk is an integral part of the TEF Scheme, ;we invite t.ie Subcommittee's attention to this second document. We are sending copies of these comments directly to all members of the Toxic Equivalency Factor Methodology Subcommittee. If there are any' questions,|please call Dr. Carol Stack (887-1196) of my staff. ` j Sincerely yours, Enclosures cc w/ encs.: Geraldine V . 1Cox, Ph.D Vice President Technical Director Members of the TEF Methodology Subcommittee i i ]i i i iI 783623 ! GENP 010812 i Attachment I COMMENTS OF THE CHEMICAL MANUFACTURERS ASSOCIATION DIBENZOFURANS/DIBENZODIOXINS PANEL ON EPA'S TOXICITY EQUIVALENCY FACTORS (TEF) SCHEME August 25, 1986 783624 I COMMENTS OF THE CHEMICAL MANUFACTURERS AcSOCIATION DIBENZOFURANS/DIBENZODIOXINS PANEL OK EPA'S TOXICITY EQUIVALENCY FACTORS (TEF) SCHEME The Chemical Manufacturers Association j(CMA) Dibenzo- furans/Dibenzodioxins Panel urges the Scientific Advisory Board to recognize two features of the Toxicity Equivalency Factor (TEF) schemes used by EPA to estimate relative toxicity of different polychlorinated dibenzodioxins and i dibenzofurans (PCDDs and PCDFs). First, none of them is truly valid, nor strongly I :| supported by scientific evidence. The relative activity of different compounds in the dibenzodioxin and dibenzofuran series varies, from species to species and from biological endpoint to biological endpoint, in ways that are not predictable with our present state of knowledge. i Second, the TEF system proposed by Barnes and Beilin, which EPA has used in several regulatory contexts, provides an approximation that can be useful for risk management purposes until more precise information can be developed. At the same time, several downward adjustments to the values attributed to certain congeners by the scheme are necessary i| to make it more consistent with the available data base. i I I I. ALL TEF SCHEMES LACK ! SCIENTIFIC VALIDITY. I I No strong scientific support exists for a TEF scheme for chlorinated dibenzodioxins and dibenzofurans We focus on the chlorodibenzofurans in this discussion, because they GENP 010814 783625 make up a substantial fraction of the PCDD/PCDF compounds present in hot exit gas streams. However, similar remarks also apply to the chlorodibenzodioxins. The compound 2,3,7,8- tetrachlorodibenzofuran (TCDF) is closely similar to 2,3,7,8-tetrachlorodibenzodioxin (TCDD) in size and shape, and according tc the paradigm currently accepted by many scientists working in this field, should exhibit similar biological activity. This follows from the theory of receptor-modulated toxicity, in which binding to a receptor protein is the first step in the process that eventually leads to the very unusual toxicities exhibited by these compounds. In his cell-culture systems, Dr. William Greenlee of the Chemical Industry Institute of Toxicology indeed found 2,3,7,8-TCDF exhibits the same potency as 2 , 3 , 7 , 8- T C D D . On the other hand, in several systems studied by Safe, et a l ., TCDF exhibits only one-tenth to three-tenths the activity of TCDD. Birnbaum, et a l ., also found in the B6C3F1 mouse that 2,3,7,8-TCDF had one-thirtieth the activi ty of TCDD when the endpoint was hydronephrosis or cleft palate in the fetuses of treated dams. Birnbaum and her co-workers also observed that the relative activities of these two compounds in that mouse strain parallels the relative rates at which they are metabolized and cleared from the body, and that clearance activity was higher in pregnant mice. 783626 .' <kT$J? * - 3- i Accordingly, at a minimum/ the relative activities of different compounds in the dibenzofurans series! depend on two' factors -- the intrinsic rejceptor-binding activity and ! ! !l the clearance rates in the organism involved. Other factors i | not yet identified may also contribute. Greenlee's cell| 1 *[ culture system is capable of little or no metabolic activ- I il ity, and expresses something nearer to thej intrinsic activ ity than do most other systems yet studied1. Conversely, the studies of Birnbaum and her colleagues 1 at i( NIEHS1 show the 'i maximal effects of clearance rate on activity. Safe and his co-workers, as well as many others, have made numerous attempts to derive a self-consistent, regular relationship between the activities of PCDDs and PCDFs so I! that reliable predictions could-be made. These! efforts are i 1| doomed to failure. EPA should not be encouraged to pursue this line of inquiry. II. THE EPA TEF SCHEME NONETHELESS HAS REGULATORY RISK MANAGEMENT! UTILITY \ \ AND THUS SHOULD BE AMENDED' SLIGHTLY | TO REFLECT AVAILABLE DATA MORE CLOSELY. 1 CMA recognizes that from time to time!circumstances will arise that require risk management decisions to be made 1 ! II on health risks posed by mixtures of PCDDsand PCDFs. Because good data will often no.t be available on a mixture ! |1 close in composition to the one- at issue, use of a TEF i scheme can be justified. i i I I G E N P 010816 783627 i I[ f4 CMA supports use of the Barnes-Bellin TEF scheme for regulatory risk management purposes. Among the several schemes which have been proposed, this one best reflects the complexity of the toxicologic issues and makes use of more of the information available than other schemes. At the same time CMA urges the Science Advisory Board to recommend minor revisions to this EPA scheme so that it will better account for well-known toxicity differences in the tetrachlorodibenzodioxins and tetrachlorodibenzofurans. The present scheme assigns a single "toxicity equiva lent" value for all TCDDs other than the 2,3,7,8-isomer. Existing data indicate, however, that the non-2,3,7,8tetrachlorodibenzodioxins are not equivalently potent. It is well known that certain non-2,3,7,8-TCDD isomers, such as the 1,3,7,8-isomer, exhibit activity in several in vitro tests. (Few in vivo results have been reported). The value assigned by Barnes-3ellin for all other TCDDs may be appropriate for these compounds. However, it is also well known that other members of this series, such as 1,3,6 ,8-TCDD, exhibit activities orders of magnitude lower than 2,3,7,8-TCDD . In guinea pigs, for instance, the L D 50 for 2,3,7,8-TCDD is 0.5 to 2.0 yg/kg, while the L D 50 for 1,3,6 ,8-TCDD is >1.5 x 10 yg/kg, that is greater than 15 grams 1,3,6 ,8-TCDD per kg body mass. Probably two-thirds of the 22 different TCDDs will be found, like 1,3,6,8-TCDD, to be practically non-toxic. G E NP 010817 783628 - 5- I I i t If all of the nearly non-toxic TCDDs were rare and the k\ more toxic isomers common, a scheme that treated all TCDDs iJ equivalently would have little adverse consequence. However, the 1,3,6,8-/1,3,7,9-TCDD pair together predominate ! among tetra isomers in environmental sources of mixed PCDDs i , '1 and PCDFs. At least these two TCDD isomersi should be I assigned a TEF value of zero. | 1| Similar considerations apply to the tetrachlorodi- ! '| benzofurans. If these compounds are to bejlumped in one category in a TEF scheme, the values assigned should reflect : j J the fact that in most mixtures 'the non-toxic isomers make up ij the majority. Similarly, the data now available on penta- 1 ll chlorodibenzofurans should bereviewed to see i;f the Barnes- Bellin value assigned to this class reflects their activity. Finally, CMA urges the SABt to recognize that the ! composition of PCDDs/PCDFs on incinerator-derived particu lates to which humans are ultimately exposed differs marked ly from the compositions measured in hot gas streams. It is likely that the particulate composition isj nearly enough i' ! ! l| constant that biological effects of this mixture could be measured directly. This would, of course, obviate the need for any indirect TEF estimate of toxicity. GENP 010818 783629 i  CHEMICAL MANUFAC1TURERS AS1SOCIATION GERALDINE V. COX. Ph.D. Vice President Technical Oirector August 22, 1986 -B-Y--H-A-N-D 'i i l1 Dr. Daniel Byrd, III Science Advisory Board, A-101-F Environmental Protection Agency 499 South Capitol St., S.W. Washington, D.C. 20460 t ,' j! ' ( Dear Dr. Byrd: >| 1I jI The Dibenzofurans and Dibenzodioxins Panel ox the Chemical Manufacturers Association (CMA) requestsij the opportunity to make a ten to fifteen minute presentation at the September 3, 1986, meeting of the Halogenatedi| Organics Subcommittee of the Environmental Health Committee of the Science Advisory Board (SAB) to be held in Kansas|City. The presentation will be made on behalf of the Panel by Dr. James Wilson. 1| The Panel has submitted comments to Dr.jDebdas Mukerjee of EPA's Office of Environmental Criteria and Assessment on the revised draft Health AssessmentjDocument for Chlorinated Dibenzofurans, which will be| the subject of the SAB meeting on September 2. A copy of those comments is attached to this letter. At the SAB meeting', Dr. 'Wilson intends to summarize briefly CMA's concerns about' the draft Health Assessment Document. ' [ i iii iii GENF 010819 783630 Formerly Manufacturing C hem ists A sso ciatio n -- Serving the Chem ical Industry Since 1872. 2501 M Street, N W W ashington, D C 20037 Telephone 202/887-1260 Telex 89617 (C M A W SH ) Dr. Daniel Byrd, Ili August 22, 1986 Page 2 We are sending copies of the CMA Panel comments on the draft Health Assessment Document directly to members of the Halogenated Organics Subcommittee. If there are any questions, please call Dr. Carol Stack (887-1196) of my staff. Sincerely yours, Enclosure cc w/enc.: Vice President-Technical Director Dr. Debdas Mukerjee Members of the Halogenated Organics Subcommittee 783631 GENP 010820 . CHEMICAL MANUFACTURERS ASSOCIATION G E R A LD IN E V. COX. Ph D Vice President Tecnm cai D irector August 22, 1986 VIA FEDERAL EXPRESS Dr. Debdas Mukerjee Project Officer for Polychlorinated Dibenzofurans Environmental Criteria and Assessment Office Environmental Protection Agency 26 W. St. Clair Street Cincinnati, Ohio 45268 Re: Health Assessment Document for Polychlorinated Dibenzofurans (51 Fed. Reg. 26052, July 18, 1986) Dear Dr. Mukerjee: The Chemical Manufacturers Association Dibenzofurans and Dibenzodioxins Panel (CMA) appreciates this opportunity to comment on the June 1986 External Review Draft of the "Health Assessment Document for Polychlorinated Dibenzo furans" prepared for the Office of Air Quality Planning Standards. CMA's comments focus upon the risk assessment in Chapter 8 of the document and the underlying health data upon which this risk assessment is based. We find that the risk assessment overestimates potential risks to chlorinated dibenzofurans by: (1) Misinterpreting the toxicology data on which it relies (the Murray three-generation 2,3,7,8-TCDD study) to conclude that 0.001 g/kg/day is a Lowest-Observed-Adverse-Effect Level (LOAEL), when in fact that dose was a No-Observed-Adverse Effect Level (NOAEL); and 3EN P 010821 783632 Formerly Manufacturing Chemists Association-- Serving the Chemical Industry Since 1872. 2501 M Street, NW Washington, DC 20037 Telephone 202/887-1260 Telex 89617 (CMA WSH) I Dr. Debdas Hukerjee August 22, 1966 Page 2 i (2) Underestimating exposures to chlorinated, dibenzofurans of persons involved in the Yusho, Japan, incident, thus overestimating potency per unit exposure In addition, we find that the document overstates by a factor of approximately 100 the likely dibenzofuran concentration in polychlorinated biphenyls found in the United|States. Each of these points are detailed in our Comments (Attachment I). ! :l The draft document does not attempt to determine a unit potency value for potential carcinogenicity of any chlorinated dibenzofurans. CMA agrees development of anyjsuchjvalue would be inappropriate given the absence of any long-term studies indicating chlorinated dibenzofurans are carcinogenic. Nonetheless, we are aware that a number of scientists have proposed development of such potency values by analogy to the carcinogenicJpotency of 2,3,7,8-TCDD. We invite your attention to this document. I| I We would appreciate your sending copies of our comments to members of the peer review panel that met in late May to discuss the chlorinated dibenzofurans criteria: document. !If there are any questions, please call Dr. Carol Stack of my staff| (202/887-1196). ! ,h Sincerely, ! Enclosures cc w/encs. I' ' :Geraldine V. Cox, Ph. !Vice President-Technical Director Members of the EPA Science Advisory Board Environmental Health Committee Halogenated Organics Subcommittee GENP 010822 783633 Attachment I COMMENTS OF THE CHEMICAL MANUFACTURERS ASSOCIATION ON EPA'S HEALTH ASSESSMENT DOCUMENT FOR CHLORINATED DIBENZOFURANS August 22, 1986 GENP 010823 783634  COMMENTS OF THE | CHEMICAL MANUFACTURERS ASSOCIATION ON | EPA'S HEALTH ASSESSMENT DOCUMENT FOR CHLORINATED DIBENZOFURANS Table of Contents INTRODUCTION ..................................... 1 1 I. THE DOSE OF 0.001 yg/kg/DAY- IN THE 1 MURRAY THREE-GENERATION TCDD REPRODUCTIVE ! STUDY WAS A NOAEL,' RATHER THAN A LOAEL ___ iiIi II. HUMAN DATA FROM THE YUSHO INCIDENT CONFIRM THAT THE REFERENCE DOSES | FOR 2,3,4,7,8-PeCDF AND 2,3;,7,8-TCDF | DERIVED FROM ANIMAL DATA ARE QUITE. > PROTECTIVE ................ ............!____ _ i! A. Detailed Data Exist onHuman Exposures to and Effects of ! PCDFs in the Yusho Incident ........... i B. EPA Misinterprets the Yusho I1 *| Data ................. 1.......... J....J 1I C. Properly Interpreted, the Yusho i Data Show an Acceptable Lifetime Average Daily Dose For;Total PCDFs of 500 Picograms/Kilogram Day .................. .................. [ III. THE CONCENTRATION OF CHLORINATED DIBENZOFURANS IN, AND POTENTIAL EXPOSURES TO, PCBS ARE OVERESTIMATED ___ _ REFERENCES ...................... .............!.... Page 1 2 5 6 8 11 17 22 fIh GET^ 010824- 783635  . & I COMMENTS OF THE ( CHEMICAL MANUFACTURERS ASSOCIATION ON , EPA'S HEALTH ASSESSMENT) DOCUMENT FOR CHLORINATED 0 IBENZ'OFURANS INTRODUCTION EPA's Health Assessment Document for Chlorinated Diben- zofurans (HAD) concludes with a1 risk asses!sment'1 that derives 'l i Reference Doses (RfDs) for two chlorinated dibenzofurans -- i1 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF. These RfDs are derived by analogy to results-of a three-generation reproductive study, i| not of any chlorinated dibenzofuran, but rather of 2,3,7,8- TCDD. EPA also compares the values determined from the TCDD data base to data from the Yusho incident m w nich humans ingested chlorinated dibenzofurans. The Agency further det e r m m e s some potential exposure routes, inicludilng exposures from polychlorinated biphenyls contaminated with chlorinated dibenzofurans. The CMA Dibenzofurans/DibenzodiLxins Panel finds flaws in each of these three aspects of the HAD. CMA considers the appropriateness of deriving any Ref erence Doses for chlorinated dibenzofurans from data on TCDD to be less than optimal. Great uncertainty exists in at-- ! i| tempting to estimate risks of one chemical based on data from another chemical. At the same time, we rebognize that ; I :| EPA has often in recent years used a Toxic|Equivalency Fac- .. 1 I 'I tor (TEF) scheme m risk management decision-making for es- timating the potency of dibenzofurans and dibenzodioxins GENP 010825 783636 I -2'- other than 2,3,7,8-TCDD given the limited data on these othI er compounds. ( ii Employment of a TEF scheme1 i*s appropriate for some reg ulatory purposes, but it always must be recognized that the use of such schemes is merely a' surrogate lIand should not be !I misinterpreted as a conclusion`that there is in fact evi dence that non-tested chemicals cause the predicted effects. Accordingly, we discuss in these comments the1 manner in which EPA employs the TCDD data to reach conclusions about I 'I chlorinated dibenzofuran potency. As detailed below, we find the Agency has misinterpreted the TCDD data on which it relies and that the effect is to calculate' an R fD that is at i least ten times too low. . I We also comment on the Agency's employment of the human data from the Yusho incident. As our detailed discussion shows, the Agency's incorrect 'interpretation o f these data leads to an overestimate of risk by more than 10 times and further demonstrates the likelihood the RfiD derived from the TCDD animal data may be too low. ! Finally, we comment on the exaggerJted estimate of chlorinated dibenzofuran exposures from potential exposures to polychlorinated biphenyls. 1 The HAD iioth ^incorrectly states the contamination level'found in U.S. commercial PCB products and inappropriately c' onstructs e'xposu'}re scenarios that fail to take into account the significant decline in i' potential PCB exposures that lias occured over the past 15 783637 I GENP 010826 3 years since manufacture was voluntarily curtailed and legis latively prohibited. 1I (1 I. THE DOSE OF 0.001 yg/kg/DAY IN THE MURRAY THREE-GENERATION TCDD REPRODUCTIVE STUDY WAS A NOAEL, RATHER THAN A LOAEL. Central to EPA's development of a Reference Dose (RfD) for chlorinated dibenzofurans is its declaration (at p. 8-4) that the three-generation Murray et al. (1979) study found I. a LOAEL for 2,3,7,8-TCDD of 0.001 yg/kg/day. To the con\ ! >| trary, 0.001 yg/kg/day was a NOAEL in this] study. I <1 The erroneous interpretation of the Murray TCDD study is based solely on statistical 're-evaluation of; the data by Nisbet and Paxton (1982) and is contrary to the interpreta tions of the study rendered by 'the original authors (Murray et al. 1979), the FIFRA* Scientific Advisory PaLel (1979), the Ontario Ministry of the Environment Expert Panel on Dioxins (1984), and essentially all experts lwho have |i evaluated that study. The overwhelming scientific opinion is that the Murray study defined the dose level1 of 0.001 yg TCDD/kg/day to be a NOAEL. A NOAEL of 0.001 yg TCDD/kg/day as dejfined in the Mur- ray multi-generation rat study also agrees withj the NOAEL of 0.001 yg TCDD/kg/day 'established in the most definitive lifetime study, by Kociba et al;. (1978) , whI ich Isubsequently | has been used by most regulatory agencies !in the derivation of long-term human exposure control limits for T C D D . As f l ' 010827 783638 < - 4- discussed in Attachment II to today's submission by CMA the same NOAEL has also been demonstrated in a variety of other toxicology studies of 2,3,7,8-TCDD. (See Attachment II, Section II). Accordingly, if one uses a long-term or lifetime expo-* sure level of 0.001 yg TCDD/kg/day as a NOAEL, application of the 3-fola and 20-fold estimates by EPA of the lesser degrees of toxicity for 2,3,4,7, 8-PeCDF and 2,3,7,8-TCDF, would lead to estimation of lifetime NOAELs for 2,3,4,7,8PeCDF and 2, 3,7,8-TCDF in the rat of 0.003 ug PeCDF/kg/day (3 times the TCDD value) and 0.02 ug TCDF/kg/day (20 times), respectively. The RfD values for human exposure to 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF can thus be established by application of a composite uncertainty factor of 100 to the NOAEL projected for the rat species. This uncertainty factor of 100 is con sidered scientifically appropriate to represent a factor of 10 for extrapolation from animal to man and another factor of 10 to account for possible interhuman response variabili ty. Thus, the RfD value for 2 ,3 ,4,7,8-PeCDF would be 0.03 nanograms/kg/day (30 picograms/kg/day). For 2,3,7,8-TCDF, the RfD value would be 0.2 nanograms/kg/day (200 picograms/ kg/day). The human LOAEL for 2,3,4,7,8-PeCDF of 0.007 ug/kg/day estimated on p. 8-6 of the HAD from Yusho data could also be used to derive short-term and long-term human exposure GENP 010828 783639 - 5- control 'limits. 1/ As the LOAEL of 0.007 yg/kg/day was es- timated for a 71-day period of exposure in humans, applica- tion of an uncertainty factor of 10 will estimate a short-term (71 day) NOAEL RfD for 2,3,4,7,8-PeCDF of ! 1 0.0007 ug/kg/day (or 700 pg/kg/day) for humans. ; To extrapo late from the 71-day short-temij RfD to lifetime, R f D , applii |J cation of an additional 10 times uncertainty factor would lead to a lifetime RfD of 70 pg/kg/ day for 2 ,3 J4,7,8-PeCDF. This calculated lifetime RfD value of 70 pg/kg/day derived from EPA's human exposure estimates for 2,!3,4,7 ,8-PeCDF is quite similar to the calculated RfD value of 30 pg/kg/day derived from the chronic lifetime animal toxicity data on 2.3.7.8- TC D D , using the 3 - f o l d T E F estimated by EPA for 2.3.4.7.8-PeCDD. ' II HUMAN DATA FROM THE YUSHO INCIDENT CONFIRM THAT THE REFERENCE,DOSES FOR 2,3,4,7,8-PeCDF AND 2,3,7,8TCDF DERIVED FROM ANIMAL DATA ARE QUITE PROTECTIVE. To attempt to confirm t h e 1accuracy o`f the Reference j| Dose developed from the 2,3,7,8-rTCDD three-|generation study, the criteria document compares the animal-derived value to a I-determination of the LOAEL for 2,3,4,7,8-PeCDF in the 1/ We note in Section II of these comments, however, that this value is not appropriate reflection of thej Yusho data of human effect levels. I GENP 010829 i 783640 - 6- I Western Japan poisoning incident. In so doing, however, EPA incorrectlv assesses that incident. As dejtailed below, the I1 human data suggest a lifetime RfD for total PCDFs in the Yusho episode of 500 picograms/kg/day, thus corroborating the appropriateness of RFD values of at least 'lo and 200 pg/kg/day for 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF,j as derived from the animal data discussed above. A. Detailed Data Exist oh Human Exposures to and Effects of PCDFs in the Yusho Incident. Persons in southern Japan ("Yusho" - 196 8) and Taiwan ("Yu-Chen" - 1976) ingested cooking oil that had been become i| contaminated with heat-transfer fluids during processing Originally thought to result pfrom the chlorobiphenyls present in the oil, Yusho symptoms have now been shown by Japanese investigators to be largely due to PCDFs present at iI ppm levels m the oil. (Masuda, et al^. , lj985; ^hen et a l ., 1985; Miyata, ej: al. , 1985; Kunita, et al., 1985.) Kashimoto, jet al. , 1985; I j More than 1,000 patients with the Yusho syndrome had been identified in Japan by 1971; a larger number were af- ' j| fected in Taiwan. People intoxicated in both incidents ex- il hibited a complex of symptoms very similar to what has been called "chloracne" when seen in industrial situations in the United States and Europe. al. , 1972.) (Kimbrough 1983; Kuiratsune, et ii i GENP 010830 783641 I I % 7' To estimate the amount ingested by persons with Yusho ; 1' symptoms, Kuratsune, et a l., surveyed 146 users of the contaminated oil, which was produced February 5, 1968, and was I distributed in 16.5 kg cans. They estimated the level of | II consumption of contaminated oil,from cooking and eating hab its. The population was divided into three dJse groups: those who consumed: (1) less than 720 ml, ( 2) between 720 and 1,440 ml, and (3) more tjian. 1,440 ml, of the contaminated oil. Ten of 80 in the low-dose group were without symp toms; all 66 in the mid- and high-dose groups exhibited ei- ' Il ther "light" or "severe" symptoms. Thirty-one of 80 in the ij low-dose group (38.8%), 31 of 45 in the mid-dose group (68.9%), and 18 of 21 in the high dose group (85 .7%), exhib ited "severe" symptoms. From these data and knowledge of the concentration of PCDFs in the oil that was ingested, an approximate ED 50 value for grade III Yusho (clinical chloracne) can be estimated. 2J The concentration of PCDFs'in the contaminated oil has been studied by Buser, et a l ., (1978), Miyata^ et a l ., (1985), Morita, et a l . , (1972).' Each group usee comparable 2/ By Kuratsune* s terminology ,j "light" symptoms correspond to clinical grades I and II Yusho symptoms! while "severe" corresponds to clinical grades'. Ill and IV. Grade III corresponds approximately to chl'oracne as it would have been diagnosed by physicians seeing workers exposed to TCDD in 2,3,5-trichlorophenol production accidents. E N P 010831 783642 1 l 8i techniques -- medium-to-high resolution gas chromatography with mass spectrometric detection, and their results are comparable. All reported concentrations of total PCDFs in the range of 1.9 to 7.4 mg/kg oil. The! high report of Miyata, et a l . , comes from a sample described as "5 February ! j !| 1968 production"; this matches the date on which the oil consumed by patients surveyed by Kuratsune, e t a l ., was reported to have been produced and shipped. : Samples described as having been produced on February 9 and 10, 1968, were estimated to contain 1.9 and 2;.3 mg/kg PCDFs, respectively. The sample examined by Morita,jet^ al. , was described as hav ing been produced February 12, 1968. Buser, et al . , gave no ! i| description of the origin of the sample they examined. Be cause of the coincidence of production dJtes, and the evi- ; i; dent decline in PCDF concentration with time o^er the period from February 5 to February 9-12, 7.4 mg PCDF/kg rice oil is a reasonable estimate of the concentrationi of these agents I in the oil ingested by the survey population. B. EPA Misinterprets the Yusho Data. As a means of checking the reliability of the RFD determined from animal data, EPA employs the Yusho data. In 1 !1 so doing, however, it fails to employ the relevant data cor rectly. E P A 's calculation is based on the following factors: GENP 010832 783643  -9 - 9: - II (1) minimum quantity to cause a grade III response of 121 ml; 1 I (2) a mean latency period of 71 days; (3) PCDF concentration in' the oil o f 3.85 ppm; and 11 I (4) a concentration of 2 ,!3,4,7,8-PeCDF ofi 8.4% of to- 1 tal PCDFs in the oil.,1 'u11 Based on these factors. EPA concludes the LOAEL for 2,3,4,7 , I: 8-PeCDF was 0.007 ug/kg/day, thus leading1 it t-o conclude 1I tI Ll that the LOAEL it derived from the animal studies of 0.0 03 : ! 1 ug/kg/day is reasonable. E P A 1s' calculations contain several errors. 1 | 1 First, no source is given for the value of 121 ml that 1 |. iis cited as "the minimim quantity ... that led! to an ob- served effect ... ." As detailed above, in the1 studies re- ported by Kuratsune, et ajL. (1972) , only estimates of the amount of oil ingested were given, and the lowest range cit- ed was "less than 720 ml." Over the period of ten or so days during which the contaminated rice-bran oil was pro duced, the concentration varied by at lea'st a! factor of ii three. Data from the Yusho reports show that o'il processed February 5, 1968 had about 7.4 ppm of tota*l PCDFs and that . j1 this had fallen to about 2 ppm by February 10. If it were not possible to relate the amount of oil ingested to the effects seen, use of the mean value would be acceptable. However, since good data are available on a population known 11 1 [ to have ingested oil produced on a particular date, oil for GENP 010833 783644 I which an analysis is available, the concentration given for this known oil should be used. Second, in using these data from the Yusho episode, the LOAEL value can be considered an approximation of the dose level that gave low incidence of the effects seen in studies of the population. Use of a single extreme value, as EPA has done, however, is improper. It incorrectly mixes risk management judgments into the risk assessment. When proper dose-response information can be extracted from the avail able data, as is the case here, it should be used to calcu late a population mean dose for the effect. Third, the work of Birnbaum (1985) and others has shown that the effects of compounds in the chlorinated dibenzofuran class are additive. In a series of experi ments, effects seen were directly proportional to the sum of the products of concentration of each compound times its relative activity in producing that effect in the animal being tested. Thus it is entirely incorrect to ignore the contributions to Yusho symptoms of compounds such as 1,2 ,3,7,8-penta, 2 ,3,4,6 ,8-penta, and 1 ,2 ,4,6 ,7,8-hexa chlorodibenzofurans. Individually, their contributions may be less than that of the 2 ,3,4,7,8 congener, but their total contributions may well exceed those of the latter. As no data are available to estimate reliably the relative activi ties of these compounds in whole animals, no attempt should GENP 010834 783645 11 I be made to estimate the relative contribution.of a single i compound to the activity of this mixture. !_3/ ; We discuss next appropriate use of the Ysho data to determine acceptable daily intakes for tjotal chlorinated (I dibenzofurans involved in the Yusho episode. ]We encourage EPA to review this assessment closely. 1 C. Properly Interpreted, the Yusho Data Show an Acceptable Lifetime Average Daily Dose of 500 Pico- j grams Total PCDFs/Kilogram/Day, , Combining the Yusho analytical, consumption and effects data demonstrates the following Effective Doses, !EDs) : (1) From the low-dose group: 4/ | !E D 39 < (0.72 1) (0.91 kg oil/1) (7l4 mg \ PCDF/kg oil)/60 kg body weight = 81 yg/kg. jj E D 39 <81 ug/kg. I* j1 3_/ In addition, it is known that the rate at which a com pound is metabolized and thus deactivated affects its activ ity in the whole animal. In a situation |such jas Yusho, where a large number of very similar compounds are present, the activity of individual compounds cannot be assessed be cause enzymes that would deactivate them if present alone may preferentially react with more reactive compounds also present. Because easily-metaboiized compounds .'are present in the body along with the more! toxic, activity!]of the less easily metabolized 2 ,3,4,7,8-pentachlorodienzofuran may be greater than it would appear to|be when tested allone. ' 1\ 4/ We assume that the rice-brn oil of Yusho has the same specific gravity as cottonseed and corn oil^s (0.91 kg/1) and that the mean body weight of th Yusho population studied by Kuratsune, et al., was 60 kg. ' |1 GENP 010835 783646 * 9 - 12 - (2) From the mid-dose group: 81 < E D 69 < (1.44 1) (0.91 kg/1) (7.4 mg/kg oil/60 kg) = 162 ug/kg. 81 ug/kg < ED 59 < 162 ug/kg (3) From the high-dose group: E D 9g > 162 ug/kg. From analyses of these data by a normal probit method, an estimate of the E D cq value for grade III Yusho can be made: 46 < E D 50 < 105 ug/kg. 5/ It would be desirable to relate the activity of this mixture to that of some single standard, such as 2,3,7,8-TCDD. However, that is problematic in this case, for three reasons. First, no isomer-specific quantitative analysis of Yusho oil has been published. The results of Buser, et a l ., suggest that more than 30 tetra-, penta-, and hexachlorodibenzofurans were present in the oil. Second, the relative activities of these different congeners are unknown, even in in vitro systems. Finally, such a congener assessment would require de termining the contribution of chlorobiphenyIs and -quaterphenyls to the activity since these were present in 5/ An EDoi estimate can also be made: 2.6 to 10 ug/kg. However, we have more confidence in the E D 50 value, as it is almost independent of the form of the dose-response curve assumed. GENP 010836 783647 13 the oil at more than one hundred times greater concentra tion, and Birnbaum, et a_l. (1985) , as previously noted, have shown that some compounds from these classes contribute to effects from PCDFs in an additive manner. It is reasonable to conclude that at least some of the PCDFs present in the Yusho oil would be more active than this aggregate dose-response estimate suggests, but it is unlikely that any would be more than ten times more so. Using the estimated low E D 50 value from the above analysis (46 ug/kg) as a point of departure for standard-setting, we thus incorporate, as detailed below, an extra order of magnitude for this uncer tainty . Employing the E D 50 value of 46 ug/kg, short-term and lifetime health advisory levels can be developed from the Yusho data. Each is explained below. Single Dose Health Advisory (SDHA) The above estimates of Effective Doses in the Yusho incident were made from exposures that occurred over a peri od of about 50 days. This period approximates the estimated half-life for these compounds in the body (King, et a l ., 1983). Because of poorer absorption and more rapid excre tion at higher dose rates, a single dose of twice that accu mulated at Yusho would have approximately the same effect. Because human data are used as the basis here for de termining a single dose health advisory (SDHA) guideline, an GENP 010837 783648 14 uncertainty factor of 1,000 applied to the E D 5q would be a quite conservative approach. One factor of ten is applied because the base dose is not a NOAEL; a second factor of ten is applied to take into account conservatively the distribu tion of susceptibilities in the population; and a third fac tor of ten to allow for uncertainties in the activity of the various PCDFs present in the Yusho oil, as mentioned above. Thus: SDHA = 2 x E D 50/lOOO = (2)(46)/1000 = 0.09 ug total PCDF/kg body weight _5 = 9 x 10 mg total PCDF/kg, or 90 ng PCDF total/kg Short-Term Health Advisory (STHA) For cumulative exposure over a 10 to 100 day period, one one-thousandth of the low E D 5q dose at Yusho can be con sidered to be protective of human health for determination of a short-term health advisory (STHA) guideline. Thus: STHA = E D 5q /1000 = 0.046 ug total PCDF/kg body weight. _5 = 4.6 x 10 mg total PCDF/kg, or 46 ng total PCDF/kg Long-Term (Lifetime) Health Advisory (LADD) A lifetime health advisory or lifetime acceptable daily dose (LADD) should be estimated taking possible accumulation of chlorinated dibenzofurans into account. That is, the intake required to reach serum concentrations equal to those 783649 GENP 010838 15 implied by the STHA dose should be estimated. However, analysis of Yusho data shows that such an analysis would require more data on human pharmacodynamics than is now available. Absent these data, use of an additional conser vative uncertainty factor of 100 applied to the STHA is ap propriate. Here, that is appropriately represented by LADD = STHA/100. Thus: 6/ LADD = 0.046 ug total PCDF/kg body weight/100 _7 = 4.6 x 10 mg total PCDF/kg/day, or 460 total PCDF pg/kg/day.*10 6/ In 1973 FDA estimated the mean oil intake of all Yusho patients to be 15 grams/day for 50 days, or 750 grams. The mean PCDF concentration is not known, but we know it to be greater than about 2 ppm (the minimum concentration reported) . Thus the mean intake of PCDFs was > (2 x 10 ) (750 g) = >1.5 x 10" 3 g = >1.5 mg. FDA assumes a mean body weight of 50 kg, and further assume that one-tenth the mean dose could be taken as a tolerable dose of PCBs. (This logic was used to derive a tolerance level for PCBs.) Following similar logic, we could define a tolerable dose for PCDFs to be >1.5 x 10~ 3 g/50/10 = 3 x lO" 5 gm PCDF/kg = 3 ug/kg. FDA reasoned that a total accumulation of less than the dose so calculated would cause no effect. This quantity was divided by 675 days (22 months) to obtain an acceptable average daily intake (AADI). Applying a similar procedure here, one would obtain an LADD of 4 x 10 3 gm PCDF/kg/day = 4 ng/kg/day. Our lower value differs from FDA's in three respects: we started with a higher "effect" dose (46ug/kg vs. 30 ug/kg) and included a much more conservative uncertainty factor to arrive at a tolerable accumulated dose (0.046 ug/kg vs. 3 ug/kg), but allowed a shorter time to reach equilibrium body burden. On balance, we believe an LADD of 500 pg/kg/day to be quite protective of human health. GENP 010839 783650 16 This LADD of 460 picograras/kg/day derived from the Yusho data for total polychlorinated dibenzofurans is higher than the LADDs derived both by analogy to the TCDD animal data (30 and 200 picograms/kg/day for 2,3,4,7,8 and 2,3,7,8, respectively, see page 4 above) and by calculations based on what EPA says is the LOAEL in the Yusho incident (70 picograms/kg/day for 2,3,4,7,8, see page 4 above). It thus supports the clear adequacy of 30 to 70 and 200 picograms/kg/day RED values derived for 2 ,3,4,7,8-PeCDF and 2,3,7,8-TCDF from animal data. III. THE CONCENTRATION OF CHLORINATED DIBENZOFURANS IN, AND POTENTIAL EXPOSURES TO, PCBS ARE OVERESTIMATED. Section 4 of the HAD also requires comment, especially in light of the misuse of some of the exposure information set forth in other sections of the report, most notably Sec tion 6.3. The Section 4 discussion of chlorinated dibenzofuran (PCDF) contamination of polychlorinated biphenyls (PCBs) is not relevant to the situation in the United States. American PCB products have consistently been shown to contain extremely low levels of PCDFs, compared to normal foreign materials, let alone the thermally stressed materi als involved in the Yusho and Yu-Cheng episodes. Numerous exaggerations and misleading statements need to be eliminat ed from the HAD. 783651 17 The errors on this issue begin in the HAD Chapter 4 discussion of potential exposures of PCDFs. On page 4-11, the statement that less than ppt levels of PCDFs were de tected in Aroclor 1016 is misleading. -The correct statement would be that no PCDFs were detected in Aroclor 1016, at a detection limit of X ppt. The next sentence is also errone ous, in that Bowes, et a l ., did not have in 1975 the analyt ical capability to detect 2,3,7,8-TCDF or 2,3,4,7,8-PeCDF in PCB formulations. At that time, as acknowledged on page 3-6, there were neither columns available to separate 2,3,7,8-TCDF from coeluting isomers nor standards to deter mine the retention time of potential interferents. On page 4-12, the statement that the composition of Kanechlor 400 resembled that of. Aroclor 1248 is also errone ous and misleading, especially since the statement implies that the Aroclor product contained the same level of contam inants as "Yusho" fluid. In fact, the fluid responsible for the Yusho incident did not even resemble Kanechlor 400, hav ing been thermally stressed and exposed to oxygen, as later acknowledged expressly in the same paragraph. On page 4-12, the HAD attributes a 2,3,7,8-TCDF concen tration of 1.25 ppm to a thermally stressed heat exchange fluid, but notes in the next sentence that at least one oth er isomer coeluted under the conditions used. Nonetheless, the 1.25 ppm value is used in Section 6.3 to calculate expo sure to PCDFs from any exposure to PCBs. GENP 010841 783652  18 All of pages 4-13 is a compilation of "suspecteds", "probablies" and "may haves". This section of the HAD thus exaggerates the contribution of PCB exposure to potential effects of PCDFs. The calculations in Section 6.3 of the HAD, purporting to estimate maximum exposure levels associated with PCB ex posure, are not realistic estimations, even assuming the desirability of developing a worst-case scenario. First, the dietary intake value, stated to represent present intake is taken from an eight-year-old paper. The quoted paper relies on data obtained before the voluntary cessation of PCB manufacture in the United States, and thus bears little relation to current potential exposures. More recent EPA and FDA evaluations clearly reflect the fact that PCB levels in fish from the Great Lakes are decreasing. A more serious error, and substantial exaggeration, is the use of 2,3,7,8-TCDF concentration in PCBs of 1.25 ppm. This value is not representative of 2,3,7,8-TCDF concentra tions in American PCB products and in fact represents the reported concentration in a severely heat-stressed and oxygen-exposed Japanese product, used under conditions known to maximize PCDF concentrations in PCBs. (See Rappe, C., et a l ., 1985) . Nor is it correct to maintain that this material is "similar to Aroclor 1248". Japanese PCB products have consistently been shown to contain higher concentrations of PCDFs, even ignoring the GENP 010842 783653 issue of heat stress. The same author who reported the val ue of 1.25 ppm in the heat-stressed Japanese product has also reported levels of PCDFs in truly representative Ameri can PCB products. (Rappe, C. et a l ., 1985). The 2,3,7,8TCDF concentrations in Aroclor 1254 and Aroclor 1260 were reported as 19 and 13 ppb respectively. Although these data are presented in Table 4-8 of the HAD, they are later ig nored in the exposure assessments. Accordingly, the HAD exaggerates potential PCDF exposures due to PCBs by a factor of almost 100 by using data not representing PCBs that could be the source of exposure to the American public. Using more realistic values for 2,3,7,8-TCDF in American PCB prod ucts reduces the value for stored 2,3,7,8-TCDF to about 0.002 ng/day, if one assumes no excretion, another exagger ated assumption. The same factor of 100 should be applied to all of the other calculated exposure levels in Section 6.3 of the HAD. The entire section thus needs to be rewritten to reflect representative exposures, even in developing worst case sce narios so popular in EPA risk assessments. The mention of exposure based on pentachlorophenol in gestion on page 6-19 is also misleading given the fact that the rest of the paragraph is a discussion of exposure to 2,3,7,8-TCDF resulting from exposure to PCBs. In the next paragraph, PCDD exposure is discussed, if only to conclude that "no firm conclusions could be reached." The rest of GENP 010843 783654 20 the paragraph is pure speculation, typified by the doublet "might possibly." The second paragraph on page 6-20 contains further ex amples of unwarranted speculation. Although generation of PCDFs as by-products of the incomplete combustion of PCBs in fire-related situations has been demonstrated in the labora tory and is substantiated by measured levels of PCDFs in building fires, the other exposure scenarios in the para graph are not realistic and certainly do not support the statement that "exposures should be investigated." The use of PCBs in casting waxes, carbonless copy papers, and heat transfer systems was voluntarily curtailed by 1972 and was expressly banned under TSCA in 1979. Such exposure scenari os are thus very unlikely. ]_/ In sum, a consistent pattern exists in Chapters 4 and 6 of the HAD of over-estimation of the contribution of PCDF contamination of PCBs to potential human exposures. A com plete rewrite of these sections of the report is necessary to reflect accurately both the actual concentrations of ]_/ In addition, there is an apparent misunderstanding of the chemistry and physical properties of PCDFs. The HAD evidences apparent surprise at the fact the PCDFs were not extracted by water from latex nipples, "unlike pentachlorophenol." Pentachlorophenol is a polar material with a measurable solubility in water, while PCDFs are insoluble in water -- thus it should clearly not. be surprising that water is not a good extractant for PCDFs. GENP 010844 783655  - 21 - PCDFs in commercial U.S. PCBs and the limited current poten tial for human exposures to PCBs. Unless such changes are made in the HAD, it will inaccurately express unwarranted cause for concern about PCDF/PCB exposures. GENP 010845 783656 REFERENCES Birnbaum, L. S., et al. , "Toxic Interaction of Specific Polychlorinated Biphenyls and 2,3,7,8-Tetrachlorodibenzo-pdioxin Increased Incidence of Cleft Palate in Mice," 72 T o x . Appl. Pharm. 292 (1985). Buser, H. R., et al_., "Polychlorinated Dibenzofurans Found in Yusho Oil and in Used Japanese Polychlorinated Biphenyl," Chemosphere 439 (1978). Chen, P. H., et a_l., "Polychlorinated Biphenyls, Dibenzofurans and QuaterphyenyIs in Toxic Rice-Bran Oil and in the Blood and Tissues of Patients with PCB Poisoning (Yu-Cheng) in Taiwan," 59 Env. Health Persoects., 59 (198 5) . FIFRA Scientific Advisory Panel, Review of Notices of Intent to Hold FIFRA Section 6 ( b ) (2) Hearing on 2,4,5-T and Silvex (Sept. 27, 1979). Kashimoto, T., et a l ., "PCBs, PCQs and PCDFs in Blood of Yusho and Yu-Cheng Patients," 59 Env. Health Perspects., 73 (1985). Kimbrough, R., in R. Tucker, A. L. Young, and A. P. Gray, e d s ., Human and Environmental Risks of Chlorinated Dioxins and Related Compounds (New York: Plenum Press, 1933). King, F. G., et al . , "Physiological Model for the Pharmacokinetics of 2,3,7,8-Tetrachlorodibenzofuran in Sev eral Species," 67 Tox. Appl. Pharm. 390 (1983). Kociba, R. J. et a l ., "Results of a Two Year Chronic Toxici ty and Oncogenicity Study of 2,3,7,8-Tetachlorodibenzo- p-dioxin (TCDD) in Rats," 46 Toxicol. A p d . Pharmacol., 279 (1978). ~ Kunita, N., et al. , "Biological Effect of PCBs, PCQs and PCDFs Present in the Oil Causing Yusho and Yu-Cheng," 59 Env. Health Perspects. 79 (1985) . Kuratsune, M. , et al . , "Epidemiological Study on Yusho, A Poisoning Caused By Ingestion of Rice Oil Contaminated With A Commercial Brand of Polychlorinated Biphenyls," 46 E n v . Health Perspects. 119 (1972). Masuda, Y., et al . , "PCB and PCDF Congeners in the Blood and Tissues of Yusho and Yu-Cheng Patients," 59 Env. Health Perspects. 53 (1985). GENP 010846 783657 Morita, M ., et a l ., "Detailed Examination of Polychlorinated Dibenzofurans in Polychlorinated Biphenyl Preparations and Kanemi Yusho Oil," 18 Bull. Environ. Contam-Tox 67 (1977) . Murray, F. J., et: a l ., "Three-generation Reproduction Study of Rats Given 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) In the Diet," 50 Toxicol. App. Pharmacol. 241 (1979). Nisbet, I.C.T. and M. B. Paxton, "Statistical Aspects of Three-generation Studies on the Reproductive Toxicity of TCDD and 2,4,5-T," 36 Ann. Stat. 290 (1982). Rappe, C., et a l ., Workshop Proceedings: PCB By-Product Formation, EPRI CS/EL-4104, July 1985. 783658 Attachment II CONSIDERATIONS FOR ASSESSING POTENTIAL HUMAN RISK FROM EXPOSURES TO 2,3,1,8-TETRACHLORODIBENZODIOXIN A Working Paper of the Dibenzof urans/D.ibenzodioxins Panel of the Chemical Manufacturers Association August 22, 1986 GENP 010848 783659 CONSIDERATIONS FOR ASSESSING POTENTIAL HUMAN RISK FROM EXPOSURES TO 2,2,1,8-TETRACHLORODIBENZODIOXIN Table of Contents _P_amdce INTRODUCTION .............................................. I. EPIDEMIOLOGY STUDIES HAVE NOT DEMONSTRATED THAT TCDD CAUSES CANCER OR OTHER LI FJC-THREATENING DISEASES IN HUMANS ................................. II. LIFETIME STUDIES OF TCDD IN ANIMALS SHOW A CONSISTENT NO-OBSERVED-ADVERSE-EFFECT LEVEL OF AT LEAST 1 NANOGRAM/KILOGRAM/DAY ............... A. Animal Toxicity Studies Have Adequately Defined the NoObserved-Adverse-Effect Levels for Non-Cancer Effects of TCDD ............... B. Lifetime Animal Studies of Chronic Toxicity/Carcinogenicity Have Established a No-ObservedAdverse-Effect Level for TCDD of at Least 1 Nanogram/Kilogram/Day .......... C. The Animal Bioassays and Other Studies on the Mechanism of Action of TCDD Show the Carcino genic Response Observed in Animals Is Reflective of a Promotion Rather than a Genotoxic Mechanism, Indicating Lifetime Human Exposure Control Limits Are Most Appropriately Derived on an "Uncertainty" or "Margin of Safety" Basis .............................. 1 4 6 7 9 11 REFERENCES ................................................ 18 GENP 010849 783660 CONSIDERATIONS FOR ASSESSING POTENTIAL HUMAN RISK FROM EXPOSURES TO 2,3,1,8-TETRACHLORODIBENZQDIOXIN A Working Paper of the Dibenzofurans/Dibenzodioxins Panel of the Chemical Manufacturers Association INTRODUCTION Numerous regulatory initiatives are being driven by the Environmental Protection Agency's (EPA's) assessment of the potential human risk posed by 2,3,7,8-tetrachlorodibenzodioxin (TCDD). Because EPA's Cancer Assessment Group has determined that a 1 in 1,000,0000 cancer risk exists for a Lifetime Average Daily Dose (LADD) as low as 6 femtograms (6 x 10 15 grams)/kilogram/day (EPA 1985), numerous regulatory initiatives have sought to control TCDD to extremely low levels. By contrast, many other nations have derived human ex posure control limits of 1 to 10 picograms (1 to 10 x 10 12 grams/kilogram/day). It is therefore important to recog nize, as detailed in this paper, the relevant scientific evidence that demonstrates the advisability of revising EPA's LADD to fall in line with the views of international experts. EPA has also employed a Toxicity Equivalency Factor (TEF) scheme to determine control limits for other chlori nated dibenzodioxins, as well as for chlorinated dibenzofurans. The Agency has further indicated the same GENP 010850 783661 # * 2 scheme may be applied to brominated dibenzodioxins and dibenzofurans. Because the TCDD toxicity determination is the base number from which these other control limits are derived, it is vitally important that the TCDD assessment be scientifically appropriate and technically supportable. The driving regulatory force of EPA's extremely low recommended control limit for TCDD is symptomatic of a gen eral over-concern about potential human toxicity of chlori nated dibenzodioxins and dibenzofurans. The United States and Europe have expended huge resources in an effort to de termine if there has been any impact on human health of ex posures to such substances, but have not found any obvious concerns given current limited exposures. Scarce and valuable resources are being devoted to examine non-obvious and less major concerns with full knowledge that zero impact can never be scientifically proven. There will always be uncertainty in the numbers, and additional effort can only reduce the uncertainty by small increments -- never elimi nate it. At the same time, EPA is implementing ever more stringent rules and requirements for dibenzodioxins and dibenzofurans under FIFRA, TSCA, RCRA, and CERCLA. CMA is concerned that there is no plan for deciding when society has reached a point of diminishing return on the use of national resources investigating alleged human problems related to dibenzodioxin and dibenzofuran exposure. Before further substantial expenditures are mandated, EPA GENP 010851 783662 3 * should reassess the health criteria upon which these regula tory initiatives are based. As one reviewer (Tschirley 1986) recently concluded: What the agency has not done -- and might be said to have a responsibility to do -- is to try to dispel the pub lic's fear on the basis of the evidence that exposure to low concentrations of TCDD in the environment appears not to have serious chronic effects on human beings. The importance of EPA'-s current determination of TCDD toxicity is illustrated by the fact that the control limits employed by EPA are about 1,000 times more restrictive than the levels determined by other international expert groups who have reviewed the same evidence. Specifically, its TCDD recommended human exposure control level is 160 to 1,600 times more restrictive tha.n the levels recommended by var ious non-U.S. regulatory agencies and expert panels, includ ing a Swiss expert group (Schlatter, et a l ., 1985); a Cana dian expert panel (Ontario Criteria Document 1985); a West German expert group (Appel, e_t a l ., 1985); and a Dutch ex pert group (Van der Heijden, et a l . , 1982). The EPA control limits are also about 10 times more restrictive than a U.S. Food and Drug Administration assessment of the same data (FDA 1983). Accordingly, the CMA Panel on Dibenzodioxins and Dibenzofurans has prepared this Working Paper discussing the GENP 010852 783663 V 4 scientific evidence that has led other expert groups to dis agree with E P A 's assessment of TCDD. In this paper, we: (1) Note the extensive human data on exposures to TCDD and their results, which find some toxic effects (especially chloracne) in highly exposed manufacturing workers and in dustrial accident victims, but no consistent data indicating any carcinogenic or other life-threatening diseases in hu mans . (2) Review the extensive animal data on TCDD with spe cial emphasis on the lifetime studies that evaluated chronic toxicity and carcinogenic potential. We also review the mechanistic and dose-response data, relied on heavily by other review panels, that indicate TCDD carcinogenicity is most appropriately considered a threshold-based phenomenon to which an "uncertainty" or "margin of safety" factor can be applied in deriving an acceptable human LADD. I. EPIDEMIOLOGY STUDIES HAVE NOT DEMONSTRATED THAT TCDD CAUSES CANCER OR OTHER LIFE-THREATENING DISEASES IN HUMANS.______________ In the late 1970's concern that TCDD impurities in var ious pesticides caused cancer, especially soft tissue sarcomas, was raised by a series of Swedish epidemiology studies (Hardell 1981; Hardell, e_t a l ., 1982; Hardell and Sandstrom 1979; Eriksson, ej: a_l., 1981; Hardell and Eriksson 1981; Axelson 1980). More recent data from studies 783664 - 5- I I of similarly exposed pesticide applicator's in New Zealand (Smith, et al., 1983; Smith, et al., 1984) and Vietnam (U.S. Air Force 1983; U.S. Air Force 1985) and forestry and agricultural workers in Sweden1 (Wiklund &| Holm, 1986) have found no such association. I I In addition, critical scientific review of the original I! Swedish studies, as well as examination of results of stud- les of manufacturing workers exposed to TI CDD 'Iin tWhe U.S. (Cook, et al. , 1980; Ott, et ail., 1980; Zack and Suskind i| 1980; Zack and Gaffey 1983) and in Europe (Theiss, et al., I 1982; Dallderup and Zellenrath 1983), have1 led most review- ers to conclude that there is <no significant epidemiology evidence of an association between TCDD aJd hum-an cancer or other life-threatening disease.' ! .' The Expert Committee (including Drs.jO. Kutzinger, G. , 1I L. Plaa, S. Safe, E. Y. Spencer and B. Birmingham) that re- tj ported to the Ontario Canada Ministry of Environment in its Scientific Criteria Document on PCDDs and PCDFs, for exam- pie, concluded (at 1-13): Epidemiological studies to date do not present sufficient evidence to establish a causal relationship between exposure to PCDDs or PCDFs and a chronicj human health effect relating to carcinogene sis, coronary disease or impairment of the immune system. [ The American Medical Association's Council on Scientif- ic Affairs (1984) similarly concluded thalt although many GENP 010854 783665 f adverse effects of dioxins had been found in 'exposed ani mals: Except for chloracne, ... TCDD has not demonstrated comparable levels of bio logic activity in man; that is to say, no long-term effects on the cardio vascular and central nervous systems, the liver, the kidney, the thymus and immunologic defenses, and the reproduc tion function -- in the male, female or offspring -- has been demonstrated. It is true that even this extensive body of epidemiolo gic data cannot prove an absence of risk for low level TCDD exposures, but no such body of data ever will exist. On the other hand, these data provide assurance that significant adverse human effects are unlikely at low exposures. These data, moreover, caution strongly against exaggerated inter pretation of the laboratory animal evidence, as discussed next, to establish guidelines for human exposure limits. II. LIFETIME STUDIES OF TCDD IN ANIMALS SHOW A CONSISTENT NO-OBSERVEDADVERSE-EFFECT LEVEL OF AT LEAST 1 NANOGRAM/KILOGRAM/DAY. Given the absence of data indicating long-term debili tating effects of TCDD exposure in man, most expert review groups and governments have sought to establish human con trol limits based on the substantial animal toxicity data base. TCDD has been tested in a variety of toxicity tests using various animal species. GENP010S^ 783666  * 7 The animal studies considered most appropriate for de termining lifetime exposure control limits for man are the lifetime animal studies evaluating chronic toxicity and carcinogenic potential. These long-term animal studies con sistently have shown a no-observed-adverse-effect level (NOAEL) of at least 1 nanogram/kilogram/day. The preponder ance of data thus supports derivation of a lifetime human exposure control limit of approximately 10 picograms/kilo- gram/day based on the existence of these NOAELs and appli cation of a 100 times "uncertainty" or "margin of safety" factor. A. Animal Toxicity Studies Have Adequately Defined the No-ObservedAdverse-Effect Levels for NonCancer Effects of T C D D . TCDD has been administered to a variety of species in standard toxicologic studies. Apart from the lifetime ani mal studies discussed next, the studies of reproductive and teratogenic effects are most significant to human health risk assessment. The Ontario Expert Committee summarized those studies (Ontario Criteria Document 1985 at 3-132) : . Data from teratological (reproductive effects) studies in rats and mice indi cate that 2,3,7,8-Ti+CDD causes embryolethality and/or fetotoxicity. A 3-generation reproduction study of rats was associated with decreased fertility and neonatal survival in the first and second generations. GENP 010856 783667  ** 8 NOELs for these teratogenic and repro ductive effects over the range 0.001 to 0.03 ug 2,3,7,8-TuCDD/kg have been re ported . As the Ontario Report further notes, TCDD has been found to affect the fetus only at doses equivalent to those which produce adult toxicity. An additional margin of safety should be inherent in any extrapolation from TCDD animal results given the data indicating the lesser sensitivity of humans. Reviews by both Neal (1983) and Tschirley (1986) found man to be less sensitive to acute TCDD effects than tested laboratory ani mals, including rats, mice and guinea pigs. Data concerning actual human exposures to TCDD confirms this analysis. Perhaps the most valuable human data for evaluating teratogenic, fetotoxic, and reproductive risk are those obtained in the Seveso region following the 1976 acci dent. Unlike other human exposures to TCDD, Seveso involved severe exposure to women of child-bearing age. The Seveso exposures caused no increase in spontaneous abortion, birth defects, or any abnormalities in the growth and development of children in utero at the time of the accident. (Kami, et a l ., 1982.*) In addition, the Kligman study which demon strated that humans voluntarily exposed to TCDD by dermal application suffered no adverse effects at doses well above those which produce chloracne in test rabbits, also suggests that people are less sensitive than test animals. GENP 010857 783668 Taking all of these considerations into account, the application of a 100-fold "uncertainty" or "safety margin" for TCDD to the NOAEL defined in the animal studies is a conservative approach to establishment of lifetime human control limits. B. Lifetime Animal Studies of Chronic Toxicity/Carcinogenicity Have Established a No-ObservedAdverse-Effect Level for TCDD of at Least 1 Nanogram/Kiloaram/Dav. Almost all reviews of the evidence of TCDD carcinogen icity in animals have focused on the Kociba, et a_l. (1978) study in Sprague-Dawley rats. This study, in agreement with other bioassays conducted in other rat strains and in mice, established a lifetime NOAEL for chronic tcxicity/ carcinogenic response of at least 1 nanogram/kilogram/day. The Kociba study is considered the most pertinent animal study for deriving long-term human exposure control limits because it was conducted with state-of-the-art procedures to evaluate the dose-response pattern for both chronic toxicity and potential carcinogenicity. Detailed pathologic examination in the Kociba study of an extensive list of tissues from rats given the high dose level of 0.1 yg/kg/day revealed the presence of toxicologic lesions. The liver was the primary target organ. Only at this highest and overly-toxic dose level, which exceeded the maximal tolerated dose and shortened the lifespan of female GENP 010858 783669 I 10 rats, was there a carcinogenic response following lifetime treatment. At the intermediate dose level of 0.01 yg/kg/day, there was no definite carcinogenic response, despite the fact that this dose was high enough to produce some toxicity. In the primary target organ, the liver, the maximal response was the formation of hyperplastic nodules originating from the liver cells. At the lowest dose level of 0.001 yg/kg/day, there was no carcinogenic response, and no other adverse effect was associated with this lifetime exposure to T C D D . NCI bioassay results in Osborne-Mendel rats are in agreement with the results observed in the Sprague-Dawley rats in the Kociba study. In the NCI study, TCDD induced liver neoplasms in female rats only at the high dose of 0.07 yg/kg/day. No carcinogenic effects were observed at a daily dose of 0.0014 yg/kg/day. TCDD has also been administered to mice in long-term studies. The report is ambiguous (Toth 1979), but even if a true carcinogenic response was produced at the middle dose level of 0.7 yg TCDD/kg/week, this dose is equivalent to the daily dose of 0.1 yg/kg/day demonstrated to be carcinogenic to rats in the Kociba study. The Toth study found no carcinogenic effects in mice at the lower dose of 0.03 yg/kg/day. Upon reviewing these lifetime studies, the Canadian experts concluded (at 1-11): 783670  11 Those studies involving oral administra tion (2,3,7,8-Ti+CDD is most toxic using this route of exposure) have reliable dose-response data and indicate clear NOELs (0.001 to 0.0014 yg/kg/day) for tumour incidence. In general, 2,3,7,8-T^CDD administration was associated with relatively few histologically different tumour types. The onset of these tumours appeared late in the study and generally at similar time to onset of similar, but less fre quent, tumors in the control animals. Although 2,3,7,8-TuCDD has been found to be carcinogenic in rats and mice, it is difficult at this stage to predict the ability of this compound to induce tumours in humans. In sum, long-term cancer studies of TCDD in several strains of both rats and mice have shown neither chronic toxicity nor carcinogenicity at lifetime doses of 1 nanogram/kilogram/day. C. The Animal Bioassays and Other Studies on the Mechanism of Action of TCDD Show That the Carcinogenic Response Observed in Animals Is Reflective of a Promotion Mechanism Rather than a Genotoxic Mechanism, Indicating Lifetime Human Exposure Control Limits Are Most Appropriately Derived on an "Uncertainty" or "Margin of Safety" Basis. Recent reviewers have deliberated on the proper inter pretation for human risk assessment of carcinogenic respons es from administration of TCDD to animals. Each of these assessments has focused on the absence of genotoxic poten tial and have identified an indirect promotion mechanism as the likely cause of the. tumors seen in laboratory animals. GENP 010860 783671 * 12 Accordingly, these reviewers have all applied an "uncertain ty" or "margin of safety" analysis to the NOAELs found in the definitive and sensitive long-term animal studies to determine human control limits. Many scientists, including Pereira (1985) of EPA, have recognized the need for differentiation between carcinogens that mechanistically interact directly with DNA (genotoxic) and those that do not (non-genotoxic) . Initiators are genotoxic agents that penetrate the cell nucleus and damage or alter the DNA genetic material of the cell. By contrast, promoters or modifying agents produce a carcinogenic re sponse as an indirect effect of organ toxicity or by impair ing the body's defense mechanisms against carcinogenic ini tiators . Current theory of some scientists assumes that the genotoxic potential of initiators may indicate the lack of a threshold for carcinogenic effects. For promoters, on the other hand, it is generally agreed that a threshold for the carcinogenic response exists (Pereira 1985) . This threshold would be indicated by the dose-response data defining the NOAEL for organ toxicity or impairment of bodily defense mechanisms. In the absence of detailed quantitative infor mation about the exact mechanism of action, most authorities thus recommend, in line with an increasing scientific con sensus, using a conservative "uncertainty" or "margin of safety" factor to protect human health. GENP 010861 783672  13 These considerations apply to TCDD, as it is generally agreed it is not a cancer initiator. Short term assays in dicate TCDD is not genotoxic. Various mechanisms of TCDD carcinogenicity have been investigated, each of which points to the conclusion that TCDD is acting as a promoting or mod ifying agent, for example, through tissue damage found at the same doses at which a carcinogenic response is observed. TCDD does not covalently bind to DNA or RNA (Poland and Glover 1979), does not induce DNA repair synthesis (Althaus, et a l ., 1982), and is essentially devoid of any mutagenic activity (Wassom 1977 ; Kociba 1984) . In an iri vivo cytogenetics screening study conducted for FDA, Green and Moreland (1975) found no chromosomal aberrations in the bone marrow of male rats treated with TCDD. A subsequent study by Green, et_ a l ., (1977) , limited by the fact that controls were not used, reported "only weakly positive" results, while an earlier study by Khera and Ruddick (1973) was nega tive for dominant lethal mutations in Wistar rats. In addition, Poland and Glover (1979) tested the DNA binding potential of TCDD in the liver of Sprague-Dawley rats and found that the maximum potential DNA binding by TCDD is 10,000 to 1,000,000 times less than that of most chemical carcinogens. They thus concluded, "it is unlikely that TCDD-induced oncogenesis is through a mechanism of covalent binding to DNA and somatic mutation." GENP 010862 783673 14 Taken together, these studies provide strong evidence that TCDD does not interact with or damage cellular genetic material to produce heritable genetic changes. TCDD is therefore unlikely to cause cancer via a genotoxic mecha nism . As the Ontario Expert Committee concluded (at 1-10): 2,3,7,8-TuCDD does not form DNA adducts, i.e., it does not chemically bind to DNA. Therefore it is unlikely to cause mutations by chemically changing DNA directly. This compound has been extensively test ed in in vitro microbial mutagenicity tests, such as the Ames test, with main ly negative results. More limited in formation is available from in vitro and in vivo mammalian test systems for mutagenicity and clastogenicity. On the other hand, considerable evidence indicates that TCDD acts through one or more non-genetic mechanisms as a promoting or modifying agent. These mechanisms depend upon the occurrence of TCDD-induced toxicity or physiological alterations which, in turn, enhance or promote the growth of tumors. Dose levels below those needed to produce toxicity or physiological alterations are unlikely to increase tumor incidence. The lifetime study of TCDD rats by Kociba, ejt a l . (1978), for example, showed a carcinogenic response only at dose levels that induced toxicity. As detailed above, the lowest dose level (0.001 yg/kg/day) was a NOAEL for such toxicity, and no carcinogenic effects were observed. It is GENP 010863 783674 15 well-known that recurrent tissue injury and repair commonly leads to tumors in affected organs of laboratory animals. Thus, one very likely mechanism for TCDD production of tu mors is recurrent tissue injury and regenerative repair within the affected organ. The non-genetic mechanisms involved in the intermediate toxic or physiological effect occurred only above the 0.001 yg/kg/day NOAEL defined in the lifetime toxicity studies. Accordingly, with lifetime exposure levels at or below 0.001 yg/kg/day, one would expect no intermediate toxicity or physiological alteration and therefore no tumor promotion. The subsequent study by Pitot, et al_. (1980) , supports the non-genotoxic interpretation. Pitot tested "the hypo thesis that the liver cancer associated with chronic admin istration of TCDD might arise from the promoting activity of the compound, presumably stimulating cells already sponta neously initiated by dietary and other environmental car cinogens." The strain of "rats and the TCDD dosage regimen" used "were chosen to resemble closely the conditions" in the Kociba study. Dr. Pitot concluded: "TCDD is a potent pro moting agent for hepatocarcinogenesis." In addition to the promotion of liver tumors in rats reported by Pitot, another study by Poland, et_ a l . (1982) reported TCDD to be a promoter of skin tumors in hairless mice after treatment with known cancer-initiating agents GENP 010864 783675 16 such as N-methy1-N-nitrosoguanidine (MNNG) or dimethylbenzonthrocene (DMBA) . Another more recent study by Abernethy, et a 1 . (1984 ) reported TCDD to be a promoter of the trans formation of C3H/IOT 1/2 cells that had been initiated with MNNG. Overall, these studies provide compelling evidence that TCDD acts as a cancer promoter in animal bioassavs. In sum, strong evidence exists that TCDD acts not by a genotoxic mechanism but rather by one or more non-genetic mechanisms that promote or enhance tumor growth. As the Canadian expert group concluded: Results of short term genotoxicity tests suggest that 2,3,7,8-THCDD is not genotoxic in a classical sense and does not act directly on the chromosomes or the DNA molecule itself. Consequently, 2,3,7,8-TwCDD appears to produce tumours in rodents by an indirect mechanism. The Ontario expert committee thus concluded that an acceptable LADD for TCDD could be derived by applying an "uncertainty" or "margin of safety" factor of 100 to the NOAEL of 1 nanogram/kg/day. This LADD of 10 picograms/ kg/day is, as noted above, consistent with other Swiss, West German and Dutch expert conclusions. In sum, based on detailed review of the available data, international experts have determined the appropriate level of concern for lifetime exposure to TCDD is 1,000 times higher than EPA has determined. Given the many Agency ini tiatives being driven by this unduly high estimate of TCDD GENP 010865 783676 * I - 17 - potency, it is imperative that EPA reassess its 1985 deter mination. GENP 010866 783677 REFERENCES Abernehy, et a_l. , "The Effect of TCDD Upon Transformation, Initiation and Promotion of C3H/10T 1/2 Cells," Abstract, 15th Annual EMS Meeting (1984). Althaus, F. R. , et a_l. , "Chemical Quantification of Unsched uled DNA Synthesis in Cultured Hepatocytes as an Assay for the Rapid Screening of Potential Chemical Carcinogens," 42 Cancer Research 3010 (1982). AMA Council on Scientific Affairs, "Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants: An Update," American Medical Association (1984). Appel, et al., 5th Intern. SvmD. on Chlorinated Dioxins, (1985) . Axelson, 0., et a l ., "An Updated Epidemiologic Investiga tion of Swedish Railroad Workers," 6 Scandinavian J, Work Environmental Health 73-79 (1980) . Cook, R. R . , et a l ., "Mortality Experience of Employees Exposed to 2,3 ,7,8-Te trachlorodibenzo-jo-Dioxin (TCDD)," 22 J. Occup. Med. 530 (1980). Dalderup, L. M . , and D. Zellenrath, "Dioxin Exposure: 20 Year Followup," 1 Lancet 1134 (1983) . EPA, "Health Assessment Document for Polychlorinated Dibenzofurans," (June 1986). Eriksson, M . , et a l ., "Soft Tissue Sarcomas and Exposure to Chemical Substances: A Case-Referent Study," 38 British J. Industr. Med. 27 (1981) . Green, S., et a l ., "Cytogenetic Evaluation of Several Dioxins In The Rat," 33 Toxicol. Apol. Pharmacol. 161 (1975). ~ Green, S., et a l ., "Cytogenetic Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin On Rat Bone Marrow Cells," 6 FDA By-Lines 292 (1977). Hardell, L., "Relation of Soft Tissue Sarcoma, Malignant Lymphoma and Colon Cancer to Phenoxy Acids, Chlorophenols and Other Agents," 7 Scandinavian J. Work Environmental Health 119 (1981). GENP 010867 783678 - 19 - Hardell, L., and M. Eriksson, "Soft Tissue Sarcomas, Phenoxy Herbicides, and Chlorinated Phenols," 2 Lancet 250 (1981). Hardell, L . , and A. Sandstrom, "Case Control Study: Soft Tissue Sarcomas and Exposure to Phenoxyacetic Acids and Chlorophenols," 39 oritish J. Cancer 711 (1979). Hardell, L., and M. Eriksson, "Soft Tissue Sarcomas, Phenoxy Herbicides, and Chlorinated Phenols," 2 Lancet 250 (1981). Hardell, L., et al., "Epidemiological Study of Nasal and Nasopharyngeal Cancer and Their Relation to Phenoxy Acid or Chlorophenol Exposure," 3 British J. Industr. Med. 247 (1982) . Khera, K. S. and J. A. Ruddick, "Polychlorodibenzo-pdioxins: Perinatal Effects -and the Dominant Lethal Test in Wistar Rats," _in Blair, E. H. (ed.) Chlorodioxir.s-Origins and Fate (1973) . Kociba, R. J., et a l ., "Results of a Two Year Chronic Toxicity and Oncogenicity Study of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) In Rats," 46 Toxicol. Apol. Pharmacol. 279 (1978). Kociba, R . , "Evaluation of the Carcinogenic and Mutagenic Potential of 2,3,7,8-TCDD and Other Chlorinated Dioxins," at 73, _in Banbury Report 18: Biological Mechanisms of Dioxin Action, (198 4) . Marni, E., et a l ., "Birth Defects Register in Seveso: A TCDD-Polluted Area," at 174 i_n Plans for Clinical and Epidemiologic Follow-up After Area-Wide Chemical Contamin ation (Washington: National Academy Press, 1982). Neal, R., Interim Report of the Missouri Dioxin Task Force, 40-41 (1983). Ontario Ministry of the Environment, "Scientific Criteria Document for Standard Development," (1985). Ott, M. G . , et a l . , "A Mortality Analysis of Employees En gaged in the Manufacture of 2,4,5-trichlorophenoxyacetic Acid," 22 J. Occup. Med. 47 (1980). Pereira, M . A . , "Mouse Liver Tumor Data: Assessment of Carcinogenic Activity," 1 Toxicol, and Indust. Health 311 (1985). GENP 010868 783679 20 Pitot, H. C., et. a_l. , ''Quantitative Evaluation of the Promotion by 2,3,7,8-Tetrachlorodibenzo-p-dioxin of Heptacarcinogenesis From DiethyInitrosamine," 40 Cancer .Res. 3616 (1980). Poland, A. and E. Glover, "An Estimate of the Maximum In Vivo Covalent Binding of 2,3,7,8-tetrachlorodibenzo--dioxin to Rat Liver Protein, Ribosomal RNA, and DNA," 39 Cancer Res. 3341 (1979) . Poland, A. et a l ., "Tumour Promotion By TCDD In Skin of HRS/J Hairless Mice," 300 Nature 271 (1982). Schlatter, C. and H. Poiger, "Assessment of Contamination with 2,3,7,8-TCDD," Institute for Toxicology, University of Zurich (1985) . Smith, A. H. , et a l ., "The New Zealand Soft Tissue Sarcoma Case-Control Study: Interview Findings Concerning Phenoxyacetic Acid Exposure," 12 Chemosphere 565 (1983) . Smith, A. H., et a l ., "Soft Tissue Sarcoma and Exposure to Phenoxyherbicides and Chlorophenols in New Zealand," 73 J . Natl. Cancer Inst. 1111 (1984). "Statement by Sanford A. Miller Before the Congressional Subcommittee on Natural Resources, Agriculture Research and Environment," U.S. Food and Drug Administration, 1933. Theiss, A. M . , et a l ., "Mortality Study of Persons Exposed to Dioxin in a Trichlorophenol Process Accident That Occurred in the BASF AG on November 17, 1953," 3 Am. J. Ind. Med. 179 (1982). Toth, K., et_ a l ., "Carcinogenicity Testing of Herbicide 2,4,5-Trichlorophenoxyethanol Containing Dioxin and of Pure Dioxin in Swiss Mice," 278 Nature 548 (1979) . Tschirley, F.H., "Dioxin," 254 Scientific .American 29 (Feb. 1986) . USAF School of Aerospace Medicine, "Project Ranch Hand II: An Epidemiologic Investigation of Health Effects of Air Force Personnel Following Exposure to Herbicides. Baseline Mortality Study Results" (Brooks Air Force Base, Texas: United States Air Force, June 30, 1983). USAF School of Aerospace Medicine, "Project Ranch Hand II: Mortality Update--1984" (Brooks Air Force Base, Texas: United States Air Force, 1985). GENP 010869 783680 - 21 - Van der Heijden, et a l ., "Evaluation of the Carcinogenicity and Mutagenicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); Classification and No-Effect Level," Report DOC/LCM 300/292, Dutch State Institute of National Health (1982). Wassom, et a_l. , "Review of the Genetic Toxicology of Chlorinated Dibenzo-p-Dioxins," 47 Mutation Research 141 (1977/1978). Wiklund, K. and L. Holm, "Soft Tissue Sarcoma Risk in Swedish Agricultural and Forestry Workers," 76 JNCI 229 (1986) . Zack, J. A., and R. R. Suskind, "The Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident," 22 J. Occup. Med. 11 (1990). Zack, J. A., and W. R. Gaffey, "A Mortality Study of Workers Employed at the Monsanto Company Plant in Nitro, West Virginia," at 575 i_n Human and Environmental Risks of Chlo rinated Dioxins and Related Compounds, eds. Tucker, R. E., et al. (New York: Plenum Press, 1983). GENP 010870 78368^ INTERIM PROCEDURES. FOR ESTIMATING RISKS ASSOCIATED WITH EXPOSURES TO MIXTURES OF CHLORINATED DIBENZO-p-DIOXINS AND DIBENZOFURANS (CDDs AND CDFs ) DRAFT Prepared for the Risk Assessment Forum U.S. Environmental Protection Agency Washington, DC A p ril 1986 AUTHORS Judith S. B e i l i n , Ph.D. Office of Solid Waste and Emergency Response Donald G. 3arnes, ph.D. Office of Pesticides and Toxic Substances TECHNICAL PANEL Donald Barnes, Ph.D. (OPTS)* Steven Bayard, Ph.D. (ORD) Irwin Baumel, Ph.D. (OPTS) Judith B e i l i n , Ph.D. (OSWER) David Cleverly, M.S. (OAQPS) Frank Gostomski, Ph.D. (OD'W/OWRS) Charalingayya Hiremath, Ph.D. (ORD) Paul Milvy, Ph.D. (OPPE) Abe Mittelman, M.S. (OSWER) Debdas Mukerjee, Ph.D. (ORD) Charles Nauman, Ph.D. (ORD) Hugh Spitzer, B.S. (ORD)* Jerry Stara, Ph.D., D.V.M. (ORD) RISK ASSESSMENT FORUM STAFF Dorothy Patton, Ph. D . , J.D., Executive Director (Acting) Alan Ehr lich, Ph. D., Executive Secretary ^Technical Panel Co-Chairman GENP 010871 783682 DRAFT-- DO NOT QUOTE OR CITE This i s a draft document for review purposes only and does not constitute Agency policy. Mention of trade names or commercial produc does not constitute endorsement or recommendation for use. GENP 010872 ii 783683 TABLE OF CONTENTS I. SUMMARY................................................................................. .. 1 I I . THE NEED FOR A PROCEDURE FOR ASSESSING THE RISK ASSOCIATED WITH EXPOSURE TO COMPLEX MIXTURES OF CDDs/CDFs. . . . CM I I I . APPROACHES TO HAZARD ASSESSMENT FORCDD/CDF MIXTURES .................. 4 A. The Ideal Approach -- Long-Term, Whole-Animal Toxicity Assay of M ixtur es.................................................................. 4 B. A Promising Approach -- Short-Term, Biological Assay of Mixtures .............................................................................. 5 C. A Reductionist Approach - - A d d i ti v i ty of Toxicity of Components ........................................................................... 5 D. An Interim Approach -- 2378-TCDD Toxicity Equivalence Factors (TZFs) ..................................................................... 5 IV. THE 2373-TCDD TOXICITY EQUIVALENCE FACTORS (TEFs) APPROACH TO ASSESSING THE TOXICITY OF COMPLEXMIXTURES OF CDDs/CDFs . . . 7 V. APPLICATIONS TO RISK ASSESSMENT.................................................13 VI. COMPARISON OF TEF APPROACH WITH RESULTS OF BIOLOGICAL TESTING........................................................................................ 15 V II . RESEARCH N E E D S ............................................................................ 17 REFERENCES........................................................................................... 19 T A 3 L E S ................................................................................................. 23 APPENDIX A: NOMENCLATURE...................................................................... A-l APPENDIX B: COMPARISON OF DIFFERENT APPROACHES TO CALCULATING 2378-TCDD EQUIVALENTS ................................... 3-1 j 010813 iii 783684  INTERIM PROCEDURES FOR ESTIMATING RISKS ASSOCIATED WITH EXPOSURES TO MIXTURES Of CHLORINATED DIBENZO-p-OIOXINS AND -DI3ENZ0FURANS (CDDs and CDFs) 1_/ I. SUMMARY The U.S. Environmental Protection Agency (EPA) i s often confronted with the need to determine the r i s k s associated with exposure to mater i a l s such as soot, incinerator fl y ash, industrial wastes, and s o i l s which contain complex mixtures of chlorinated dibenzo-p-dioxins (CDDs) and chlorinated dibenzofurans (CDFs). Recognizing the public and toxicological concern generated by these chemicals and the s i g n i f i c a n t gaps in our a b i l i t y to evaluate the human health potential of these compounds by exi sti ng procedures, the CDD/COF Technical Panel of the m Risk Assessment Forum (Forum) i s recormending an interim method to aid in the assessment of the human health r i s k s posed by mixtures of CDDs/CDFs until data gaps are f i l l e d . The Technical Panel has reviewed' a spectrum of approaches for making such assessments, consistent with EPA's Guidelines for the Health Risk Assessment of Chemical Mixtures and has concluded that a direct biolo gica l assessment of the to xi c it y of complex mixtures of CDDs/CDFs i s preferred . A validated bioassay that can plausibly be applied to such mixtures is not now available, although promising research i s in progress in the area. An alternative approach involves - e x p lic it analysis and toxicological determination of each of the constituent CDD/CDF congeners. The data required for such an approach also need to be developed and are not l i k e l y to be generated soon. The Forum therefore concludes that, as an interim science policy measure, a reasonable estimate of the toxic \J See Appendix A for the nomenclature and conventions used in th i s paper. GENP 010874 l 783685 r is k s associated * * t h a mixture of CDDs/CDFs can be made by taking into account the d is t ri bu ti on of COO/CDF congeners or homolugues and the l i k e l y relative t o x i c i t y of these compounds. This document describes the recommended interim procedure for generating the "2378-TCDD equivalence" of complex mixtures of CODs/CDFs, based on congener- or homologue-specific data, and for using such information in assessing ris k . (The recommendations are summarized in the rightmost column of Table 1.) The Forum acknowledges that thi s procedure is not based on a thoroughly established s c i e n t i f i c foundation. Instead, the approach represents a consen sus recommendation for interim science policy, subject to change as additional data are available. The approach is judged to be applicable to mixtures of CDDs/CDFs, but should not be construed as being applicable as well to mixtures of other chemicals. The basis of th i s approach, i . e . , the assignment of t o x i c i t y equivalence factors (TEFs) is subject to revision as new s c i e n t i f i c data become available in the future. Consequently, r is k assessors and risk managers are urged to use informed dis c re ti on , noting sp ec ifi c problems on a case-by-case basi s, when deciding to which si tua ti ons the procedure can be applied. The Forum urges the support of research to broaden the s c i e n t i f i c basis for th i s approach and develop the more preferred approaches. I I . THE NEED FOR A PROCEDURE FOR ASSESSING THE RISK ASSOCIATED WITH EXPOSURE TO COMPLEX MIXTURES OF CDDs/CDFs During the late 1970s, the Agency was faced with assessing the human health significance of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). 783686 2 GENP In preparation for the cancellation hearings for the herbicides 2 , 4 , 5-t ri c hi o ro phenoxyacetic_ acid_( 2 ,4,5-T) and Si lvex, the Agency generated r is k assessments for several toxic responses for 2 , 3 , 7 ,8 -TCDD. The quantitative cancer risk assessment developed by the Carcinogen Assessment Group was later adapted for use in the Water Quality C ri te r ia (WQC) Document for 2,3,7,8-TCDO (U.S. EPA, 1984a). In addition to carcinogenicity concerns, the WQC document contains an assessment of systemic to x i c i ty based on reproductive effects resulting from exposure to 2,3,7,8-TCDD. Later, i t became clear that exposure si tuations exist in the country which involve more than 2,3,7,8-TCDD alone. Data on emissions from combustion sources (e.g., hazardous waste and municipal waste i n c i n e r a t o r s ) and contents of waste from certain industrial production processes indicate that the majority of the 75 CDDs and 135 CDFs can be detected in the environment. In recent years, the reporting of at least homologue-specific data for the CDDs and CDFs has become commonplace, and the Agency has taken some steps to address the si gni fic an ce of these findings. For example, the current draft of the Health Assessment Document for Polychlorinated Dibenzo-p-Dioxins prepared for the Office of A ir Quality, Planning, and Standards (U.S. EPA, 1984b) contains a quantitative r is k assessment for a mixture of hexachlorodibenzo-p-dioxins (HxCDDs) based on carcinogenicity studies conducted by the National Cancer Instit ute . These concerns have also led to regulatory action; e.g., several industrial wastes containing tetra-, penta-, hexachlorodioxins, and -dibenzofurans were recently designated by the Agency as EPA hazardous wastes. Faced with increasing amounts of isomer- and homologue-specific data, and recognizing the s i g n i f i c a n t potency and st r u c t u r e - a c t i v i t y relationships exhib- GENP 010876 3 783687 ited in in vi-yo and in vit ro studies of CDDs and CDFs, the Technical Panel per ceives a need to address more generally the potential r i s k s posed by the con geners other than 2,3,7,8-TCDD and the mixture of HxCDDs. Zj Detailed considera- > ation of the t o x i c i t y of the vast majority of the CDDs/CDFS is limited by the lack of a complete toxicological data base on most of the congeners. Further, i t is unlikely that many long-term test results will be available soon. For example, research on 2,3,7,8-TCDD has been under way for more than two decades at an estimated cost of more than one hundred m illion d ollars . Although this chemical has been investigated to a much greater extent than any of the other CDDs/CDFs, unanswered questions remain. Therefore, the Forum believes that an interim science policy position should be adopted for use in assessing r is k s associated with CDD/CDF mixtures, until more d e f i n i t i v e s c i e n t i f i c data are available. I I I . APPROACHES TO HAZARD ASSESSMENT FOR CDD/CDF MIXTURES A. The Ideal Approach -- Long-Term, Whole-Animal Toxicit y Assay of Mixtures Under ideal conditions, an assessment of the t o x i c i t y of a mixture of chem i c a l s is best accomplished by direct evaluation of i t s toxic effects, e.g., by determining the effects of chronic exposure in an experimental animal (U.S. EPA, 1985). Such an assessment is time-consuming and costly and would theoretically 2/ In the early 1980s, the Agency developed a method for an approximate assessment of the r i s k s of the emission of CDDs/CDFs associated with the high-temperature incineration of PCBs and combustion of municipal waste (U.S. EPA, 1981; U.S. EPA, 1982); see Table 1. The procedure presented in this document is a refinement of that approach. A comparison of a variety of methods is included in Appendix B. G E N P 010877 4 783688 have to be performed for each of the many mixtures of environmental importance. Therefore, this idealized approach would cause unacceptable delays in addressing the potential health r is k s associated with exposures to CDO/CDF mixtures. B. A Promising Approach -- Short-Term, Biological Assay of Mixtures An alternative, and perhaps more achievable, approach to hazard assessment of a mixture is a short-term assay that i nd ire ctl y provides a measure of the mixture's potential t o x i c i t y . In the case of mixtures containing CDDs and CDFs, short-term assays are under development that d ir e c t l y determine the 2.3.7 .8 - TCDD-1ike response which could be used as a measure of the t o x i c i t y of the mixture as a whole. Such assays, which take advantage of the si m il a r t o x i c ^ end points induced by CDDs and CDFs, and have been used to assess the potential health hazards of exposure to CDD/CDF-contaminated soot from PCB f i r e s (Eadon, 1982; Gierthy and Crane, 1984; Gravitz et a1., 1983), and for predicting the potential to x i c i ty of incinerator fl y ash (Rizza rdi ni, et al ., 1983; Sawyer, et al ., 1933). The development of such "mixture assays" is progressing rapidly. While additional work is required to more f u l l y validate the assay findings for spec ifi c toxic end points, especially chronic effects, and aspects of pharmacokinetics need to be considered, an increasing body of data demonstrate correlations with subchronic effects of CDDs/CDFs (Safe et a l . , 1985). The Forum, recognizing the importance of this approach in implementing it s regulatory strategy for 2.3.7.8- TCDD-like chemicals, strongly encourages research in this area. C. A Reductionist Approach -- A d d i t i v i t y of Toxi city of Components In the absence of a f u l l y developed "mixture ass ay," the components in a mixture of CDDs and CDFs could the or e ti ca ll y be i den ti fi ed and quantified GENP 010878 5 783689 by analytical chemists. Then the t o x i c i t y of the mixture could be estimated by adding the, t o x i c i t y contributed by each of it s components. In the case of most environmental mixtures, however, th is method would be of limited value since congener-specific analyses for the 75 CDDs and 135 CPcs potentially present in the mixture are seldom available. In addition, there is l i t t l e information available on the toxic potency of most of these congeners. Therefore, th is approach is not viable at this time; nor is i t l i k e l y to be feasible in the near future. 0. An Interim Approach -- 2373-TCQD Toxicity Equivalence Factors (TEFs) The Forum recommends a fourth alternative for estimating the r i s k s a s s o c i ated with exposure to complex mixtures of CDDs/CDFs. In th i s approach, as in * approach C above, information is obtained on the concentrations of homologues and/or congeners present in the mixture. Then, using the available t o x i c o l o g ical data and reasoning on the basis of st r u c t u r e - a c t i v i t y rela ti ons , the s i g nificance of the exposure to each of the components is estimated and expressed as an "equivalent amount of 2378-TCDD." Combining this information with hazard information on 2 , 3 , 7 ,8 -TCDD, and assuming a d d i t i v i t y of effects, the r i s k s associated with the mixture of CDOs/COFs can be estimated i f exposure is known. Key to the approach are the 2378-TCDD Toxicity Equivalence Factors (TEFs) which are derived in Section IV. The general approach using TEFs as outlined here is not unique; several organizations have used simi la r approaches (see Table 1). At one extreme, all CDDs/CDFs could be assumed to be as toxic as 2,3,7,8TCDD (all TEFs = 1). This position is not recommended since the limited long term data (2-year cancer bioassays) on 2,3,7,8-TCDD and a mixture of 2378-HxCCDs 6 783690 (and the greater b^dy of short-term data on many COOs/COFs) indicate that such an assumption is overly conservative. At the other extreme one could to ta ll y ignore the presence of COOs/COFs other than those for which adequate long-term data are available (most TEFs = 0). This position is not recommended in light of the similar toxic properties of several of these compounds and the structurea c t iv i t y relationship demonstrated for effects resulting from less than lifetime exposures. Instead, the Forum recommends that the TEF procedure presented below be adopted as a matter of science policy on an interim basi s, subject to revision as new experimental data become available. Based on the available s c i e n t i f i c information, the Forum believes that th i s approach represents an appropriate 4 means of approximating the potential r is k of exposure to mixtures of CDDs and CDFs for purposes of ris k management. The approach will enable the Agency to deal with many, but not a l l , of i t s problems; e.g., assigning p r i o r i t y to Superfund s i t e s , estimating the extent to which a hazardous waste site should be cleaned up, guiding decisions on which manufacturing wastes can be delisted as EPA hazardous wastes, and estimating r is k s associated with the emission of COOs/COFs from combustion sources. The remainder of this document discusses the TEF approach in greater de ta il , i l l u s t r a t e s i t s use in r is k assessment, and i d e n t if i e s additional research, the results of which would provide information for adjustments to this interim approach. IV. THE 2378-TCDD TOXICITY EQUIVALENCE FACTORS (TEFs) APPROACH TO ASSESSING THE TOXICITY OF COMPLEX MIXTURES OF CODs/CDFs 2,3,7,8-TCDD is one of 75 CDDs. Exceptionally low doses of this compound e l i c i t a wide range of toxic responses in many animals., e.g., adverse reproduc- GENP 010880 7 783691 tive effects, thymTc atrophy, and a "wasting syndrome" leading to death. The EPA's Carcinogen Assessment Group (CAG) has determined that there is su ff ic ie nt evidence to conclude that 2,3,7,8-TCDD and a mixture of two 2378-HxCODs are probable human carcinogens. The CAG quantitative assesssment indicates that these chemicals are among the most potent animal carcinogens evaluated by the Agency to date. Limited data suggest that some of the other CDDs may have other toxic effects simi la r to those of 2,3,7,8-TCDD, again at very low doses. Moreover, these to x i c i ty concerns are not restricted to CDDs. Limited experimental data, supplemented by st ru ctu re /a cti vit y rela ti ons hi ps in in vit ro tests that are correlated with in vivo toxic effects of CDFs indicate that some of these compounds exhibit "2,3,7,8 -TCDD-like" t o x i c i t y (3andiera et a l . , 1984;* Okey et al., 1984; Safe et a l ., 1985). The biochemical mechanisms leading to the toxic response res ult in g from exposure to CDDs and CDFs are not known in detail. However, experimental data have accumulated which suggest that an important role in the development of systemic t o xi c it y resu lting from exposure to these chemicals is played by an i n t r a c e l l u l a r protein, the Ah receptor, the putative product of a gene locus designated Ah. This receptor binds halogenated p oly cyc li c aromatic molecules, including CDDs and CDFs. It has been postulated that the. Ah locus controls several pleiotropic responses: a limited, but widely expressed gene complex that includes the structural genes for AHH expression, and, in a few organs, such as skin and thymus, a second gene complex regulating cell p ro li fe r at io n and d if fe re n ti at io n (Knutson and Poland, 1980; Neal, et a l . , 1982; Greenlee et al ., 1985a). In several mouse s t r a i n s , the expression of t o x i c i t y of 2,3,7,8-TCDDrelated compounds, including cle ft palate formation, l i v e r damage, effects on GENP 010881 8 783692 body weight gain. hymic involution, and chioracnegemc response, has been cor related with their binding a f f i n i t y for the Ah receptor, and with thei r a b i l i t y to induce several enzyme systems, some of which have been linked to the expres sion of carcinogenicity (Poland and Knutson, 1982; Bandiera et a l. , 1934; Madhukar et a l. , 1984; Poland et a l . , 1985; Safe et a l . , 1985; Vickers et al., 1985). St r uc tu r e -a c ti v it y studies also li n k the enhanced in v i t r o cell d i f fe re n t ia ti on caused by these compounds to the presence of the Ah receptor (Greenlee et al., 1985b). However, it has also been noted that the c yt os ol ic receptor concentration alone may not be the sole determinant of the capacity for AHH induction (Neal, 1985; Okey and Vella, 1984). In interspecies comparisons there are poor correlations between the amount of c e l l u l a r Ah receptor, i t s a b i l i t y to bind 2 , 3 , 7 ,8 -TCDO, and AHH induction (Denison and Wilkinson, 1985; Gasiewicz and Rucci, 1934; Neal, 1985); and in the mouse the development of TCDD-induced l i v e r to xi c it y cannot be ascribed sol el y to the presence of the Ah receptor (Greig et al ., 1984). A recent review concludes that although there are inconsistencies across species in the Ah receptor's being the sole mechanism of t o x i c i t y of CDDs and CDFs, the data suggest that the binding of these compounds to the receptor is in some way related to some of the biological effects they cause in experimental animals (Neal, 1985) Table 2 summarizes information on a variety of end points e l i c it e d by CDDs/ CDFs: acute t o x i c i t y , carcinogenicity, reproductive eff ects, receptor binding, enzyme induction, and in vit ro cell transformation. For ease of comparison, the data are normalized to unity for 2,3,7,8-TCDD. For example, 2378-HxCDDs have about 5% the Ah receptor binding strength of 2,3,7,8-TCDD. Their repro- GENP 010882 9 783693  ductive to x i c i ty and carcinogenic potency are, respectively, about 1% and 4 that of 2 , 3,Z,8-TCDD. Kociba and Cabey (1935) recently presented similar data. The struc tur e/a cti vit y generalizations based on the data in Table 2 sup port the generalizations in the l i te ra tu r e concerning the congeners that are most l i k e l y to be of toxic concern (Poland and Knutson, 1982; Gasiewicz and Rucci, 1984; Bandiera et a l ., 1984). That i s, congeners that are substituted in the lateral 2, 3, 7, and 8 po sitions are l i k e l y to exhibit toxic effects at lower doses than other congeners. This includes the 15 te tr a -, penta-, hexa- and heptachlorinated CDDs and CDFs l i st e d in Table 3. 3/ 3/ The Technical Panel is aware that some investigators (e.g., Grant, 1977; Olie et al , 1983; Commoner et a l. , 1984; and Ontario, 1982, 1934) have broadly defined congeners of concern to include those t r i - to hepta- congeners which are substituted with at least three chlorines in the four lateral (2, 3, 7, and 3) po sitions. The t o x i c i t y data (Table 2) do not argue strongly for this extended range of concern. Further, the increased level of complexity invoked by including these additional congeners is to suggest a greater level of accuracy and re s o lu tion than the Technical Panel believes is presently warranted by the TEF approach. The Technical Panel is also aware that receptor binding data suggest a r e l a tiv e ly high potential t o xicity for 1,2,4,6,7-PeCDF. Examination of stereochemical models show that the 4 and 6 positions of CDFs exhibit partial overlap with the lateral chlorine groups of 2,3,7,8-TCDO (Bandiera et a l . , 1984). However, th i s increased receptor binding a c t i v i t y is not reflected in an increased potency of 1,2,4,6,7-PeCDF as an enzyme inducer (cf. Table 2), an end point which has been shown to correlate with subchronic t o x i c i t y (Safe et a l . , 1985). Therefore, the Technical Panel i s treating 1 , 2 ,4 ,6',7-PeCDF as a ,,non-2378-congener1' at this time; however, additional data could lead to a change in t h i s position. 1,2 ,3,6 ,7- and 2,3,4,6,7-PeCDF are almost as potent as 2378-PeCDF in the induction of AHH a c t i v i t y in human lymphoblastoid c e l l s in v it r o (see Table 2). However, because thi s assay seems to y i e l d relative potencies that do not agree with other short-term te sts, and because dose-response`data are not ava ilable for this assay, these data are not included in the overall evaluation at the present time. 10 783694 The "2 378-TyD equivalence factors" (TEFs) li ste d in Tables 1 and 3 were assigned usirvg the-fol 1 owing c r i t e r i a : 1. Information on carcinogenic potency based on long-term animal studies takes precedence. 2. Where carcinogenic a c t iv i t y has not been demonstrated, information on systemic effects is used in the following manner: a. Data on reproductive effects take p r i o r i t y because of the s i g n i f icance of the end point in humans and because the estimated human exposure levels potentially resulting in reproductive and c a rc in ogenic effects are very similar. b. Data on acute l e t h a l i t y -is accorded very low p r i o r i t y since a c o r relation between LD5 QS chronic effects has not been established for these compounds. c. The data currently available on systemic effects (e.g., body or or^a weight losses, hepatotoxicity) are not s u f f i c i e n t for use in developing TEFs. Such data are used to provide q u al it a ti ve support for these assignments. 3. In the interpretation of the data from in v it ro test systems, more weight is placed on data from receptor binding interaction and oxid a tive enzyme induction, because for these effects the correlations with in vivo systemic effects ( immunotoxicity, body -weight loss) are st r o n g est . The above c r i t e r i a were applied as follows: 1. Since the primary concern is with chronic effects, the relative carcinogenicity responses (Table 2) for 2 , 3 , 7 , 3-TCDD and the mixture of two 2378-HxCDOs 4/ were used to generate the TEF for 2378-PeCDD. The TEF for 2378-PeCDD (0.5) is the arithmetic mean of the c a rc i n ogenic potency values for 2,3,7,8-TCDD (1) and 2378-HxCDOs (0.04). Data on receptor binding, enzyme induction, and cell keratinization generally support this value. 2. 2,3,7,8-TCDF i s assigned a TEF of 0.1 primarily because i t is 1 to 2 orders of magnitude (OMs) less potent than 2,3,7,8-TCDD in reproductive to x i c i ty te sts . Also, i t is about one 0M less potent than 2,3,7,8-TCDD in the in v i t r o tests. 3. The 2378-PeCDF congeners are assigned a TEF of 0.1 due to the responses seen in in v i t r o tests. Greater reliance was placed on the animal 4J See Appendix A, item 6 , for explanation of notation. 11 GENP 010884 783695 enzyme induction studies due to the more s i g n i f i c a n t correlations observed between thi s end point and subchronic responses than have been observed with the receptor binding end point. The human cell data were accorded less weight because these experiments were conducted at only one exposure concentration. 4. Because in v it r o data in general show HxCOFs to be about one tenth as potent as PeCDFs, their TEF is assigned a value of 0.01 (0.1/10). Further, the data generally suggest that CDFs are somewhat less toxic than the analogous CODs. Therefore, the TEF for 2378-HxCDFs should be less than that of the 2378-HxCDDs (0.04). 5. The 2373-HpCDOs and 2378-HpCDFs are assigned TEFs 3 OM less than that for 2,3,7,8-TCDD because the enzyme induction potencies of these congeners d i f f e r from that of 2,3,7,8-TCDD by about th i s factor. 6 . Based on the data in Table 2, the non-2 373-sjostibated isomers are 1 to 3 OMs less potent than the 2373-substitubed isomers. Since these data are limited to in v i t r o systems, a factor of 0 . 0 1 is ap plied to the non-2378-substituted, as compared to the 2378-substituted congeners. * With the exception of 2,3,7,8-TCDD, the 2378-HxCDDs, and 2378-TCDF, the TEFs are not based on the results of major animal (reproductive, carcinogenic) studies. Generally, TEFs are based on estimates of the r e la ti v e t o x i c i t y in in v it ro tests whose relationship to the chronic effects of concern is largely presumptive. However, as discussed above, studies on systemic effects continue to reinforce the view that the short-term assays provide important fundamental information on the t o x i c i t y of the CDDs/CDFs. In summary, the Forum concludes that there is a s u f f i c i e n t l y plausible basis for the TEF approach of estimating r i s k s associated with exposures for CDDs/COF and recommends that the Agency adopt the approach, on an interim basis, as a matter of science policy. The TEFs should be revised as additional s c i e n t i f i c information i s developed. It should be noted that th i s general approach to estimating such CDD/CDF r is k s has been taken by other regulatory groups (see Table 1 and Appendix B). GENP 010885 12 783696 V. APPLICATIONS ID RISK ASSESSMENT In general, an assessment of the human health r i s k of a mixture of CQDs and CDFs, using the TEF approach, involves the following steps: 1. Analytical determination of the CDOs and CDFs in the sample. 2. M u l ti p l ic a ti on of congener concentrations in the sample by the TEFs in Table 1 to express the concentration in terms of 2378-TCDD equivalents. 3. Surmation of the products in step 2 to obtain the total 2378-TCDD equivalents in the sample. 4. Determination of human exposure to the mixture in question, expressed m in terms of 2378-TCDD equivalents. 5. Combination of exposure from step 4 with t o x i c i t y information on 2,3,7,8TCDD (usually carcinogenicity and/or reproductive effects) to estimate r is k s associated with the mixture. In cases in which the concentrations of the 15 congeners of concern are known 2378-TCDD Equivalents = (TEF of each 2378-CDD/CDF congener x the concentration of the respective congener) + (TEF of each non-2373 CDD/CDF congener x the concentration of the respective congener) Samples of this calculation for several environmental mixtures are provided in - Table 4. In cases where only the concentration of homologous groups is known, i . e . , no isomer-specific data are available, different approaches are possible. For example, the assumption that the 2378-congeners of concern constitute all of the CDDs and CDFs present in the mixture is l i k e l y to provide an upper-bound, most conservative estimate of the t o x i c i t y . Alte rnativ ely, one could assume 13 GENP 010886 783697 that the occurrence of each of the congeners in the mixture has equal pro bab il ity (01ie et a l ., 1983; Commoner et a l ., 1984). For instance, 2,3,7,8-TCDD is one of 22 possible TCDOs and would constitute about 4% of a mixture of isomers occurring with equal probability. In other si tua ti ons p a r t i c u l a r knowledge of chemical reaction parameters, process conditions, and r es ul ts from related studies (e.g., congener d is t r i b u t i o n s in emissions from combustion sources) might enable one to estimate the rel at iv e occurrence of 2378-congeners. How ever, one must be careful to e x p l i c i t l y explain and j u s t i f y whatever assumptions are made. Table 5 i l l u s t r a t e s the resu lts obtained using different methods to estimate the proportion of 2378 to non-2378 isomers in the absence of analytical data for individual isomers. The calculated 2378-TCDD equivalents can then be used to assess the health ris k of a mixture. As an e x p l i c i t example, consider a municipal soli d waste (MSW) combustor whose particulate emissions, the CDD/CDF mixture in question, are the same as the e l ec tr ost at ic p rec ipi ta tor (ESP) catch cited in columns 5 and 6 of Table 4. The sample is estimated to contain 32 ppb 2378-TCDD equivalents; i . e . , 32 picograms of 2378-TCDD equivalents per milligram of mixture. Suppose that an exposure analy si s indicates that a person l i v i n g downwind from the incinerator receives an average d ai ly dose of 1 ng of the mixture/kg body weight resu lting from inhalation ( i . e . , without consideration of other possible routes of exposure). This exposure estimate is combined with the upper-bound carcinogenic potency of 2,3,7,8-TCDD (1.6 x 105 per mg/kg-day [U.S. EPA, 1984c]) to generate the upper 95% limi t of the excess r is k of develop ing cancer (from inhalation exposure alone) for a person l i v i n g downwind from the f a c i l i t y emitting the mixture under consideration, assuming lifetime expo sure: GENP 010887 14 783698 Upper 95i 1imi_t of excess cancer r is k resulting from inhalation exposure * [potency] x [exposure] = [1.6 x 105 per mg 2 , 3 , 7 ,8 -TCDO/kg-day] x [32 pg TCOD/mg mixture x 10" 9 mg 2, 3 ,7 , 8 -TCDD/pg x 1 ng mixture/kg-day x 1 0 " 6 mg mixture/ng mixture] VI. COMPARISON OF TEF APPROACH WITH RESULTS OF BIOLOGICAL TESTING A limited number of in vivo and in v it ro approaches have been employed in assessing the t o x i c i t y of complex mixtures of CDDs and CDFs. While the res ults from these attempts are net d e f i n i t i v e , it is in st r uc ti v e to compare those results with the re s ul ts from the TEF approach proposed here. Eadon et a l . (1982) investigated the t o x i c i t y of CDD/COF-contaminated soot associated with a f i r e involving PC3-containing e l e c tr ic a l equipment. Using the res ults from acute in vivo t o x i c i t y (LD5 Q) studies in which the soot was the test substance, the researchers determined that it had the acute t o x i c ity expected of material containing about 50 times the amount of 2,3,7,8-TCDD actually found by GC/MS analysis. Table 5 i l l u s t r a t e s the results of employing the TEF approach through three different procedures, each of which depends upon the results of GC/MS analysis of the soot. In the f i r s t instance (A, in Table 5), the analytical data have been consolidated to tot als within a homologous clas s. These con centrations are treated as i f they consisted completely of 2378-members of the class and, therefore, are multiplied by the TEF appropriate for the 2378-mem bers of the c l as s . The resu lting estimate of 2378-TCDD equivalents by th is procedure is about 80. 783699 15 G N P 01088 In procedure_S the assumption is made that the occurrence of each of the c o n f e r s in"a homologous class i s equally probable; e.g., the concentrt ion of 2,3,7,8-TCDD i s 1/22 (about 5) of the concentration of the total TCDDs. This approach leads to an estimate of the total 2373-TCDD equivalents of 8 . A rather unique data base e xi st s in the case of the soot from thi s f i r e in that an extensive iscmer-specific analysis of the sample i s available (as cited in Des Rosiers, 1984). Therefore, the full array of TEFs from Table 1 (using the current EPA recommendations) can be applied. This procedure (C in Table 5) resu lts in an estimate of roughly 50 for the total 237S-TCDD equivalents in the sample. As might be expected, the most conservative of these procedures, A, leads * to the highest estimate. Approach 3 (using theoretical pro bability of occur rence) leads to an estimate that is about 1 0 -fold lower than the isomer-specific results C, refle cti ng the fact that the 2373-congeners are present in somewhat higher than "equal p ro b ab ili ty " proportions in thi s par ticu lar soot sample. Given the complexity of the analysis involved, the approximate nature of t.ne TEF method, and the vagaries of the assay, a major feature of note in Table 5 regarding the soot samples i s that the r es ul ts of procedures A, 3, and C span a range of only one order of magnitude and bracket the bioassay estimate. In a separate study, Sawyer et al. (1983) published r es ul ts of honologuespec ifi c COD and CDF concentrations in f l y ash from four municipal solid waste combustors which are amenable to treatment by the TEF methodology. In addition, extracts from the f l y ash samples were analyzed by three bioassay techniques (AHH induction, EROD induction, and receptor binding). These data suggest that the TEF approach i s l i k e l y to be a useful interim tool for the rough (order of magnitude) estimation of the t o x i c i t y of complex GENP 010889 16 783700 mixtures of CDOs and CDFs. The a v a i l a b i l i t y of additional data comparing the results of aFvalyti-eal and biological assays will enable a conclusion regarding the preferred method of estimating TEFs (e.g., method A or B of Table 5). V I I . RESEARCH NEEDS The Forum recommends that research be conducted that will enable the develop ment of assays to d ir e c tl y assess the t o x i c i t y of mixtures of CDDs and CDFs. In addition, research should be conducted in order to provide a firmer basis for, and to guide appropriate modification of the TEF approach. The following areas of research are appropriate for these purposes: 1. Validation and completion of the in vit ro test data such as those liste d in Table 2. 2. Investigation of the rel at ionships between short-term in vivo and i n v it ro tests and the toxic end points of concern; i . e . , carcinogenic it y, reproductive t o x i c i t y , immunotoxicity, and other s i g n i f i c a n t human health effects resu lting from CDD/CDF exposure. 3. Determination of the toxic potencies of metabolites of CDDs and CDFs in in v it ro tests, r ela ti ve to the potencies of the parent compounds. As pointed out by several reviewers, this would enable a refinement of the TEF approach. 4. Investigation of additional short-term assays which can test the mech a ni st ic hypotheses underlying the TEF approach. 783701 17 GEN P 010890 REFERENCES Bandiera, S . ; et a l . (1933) Competitive binding of the c yt os ol ic tetrachlorodibenzo-p-dioxin receptor. Biochem. Pharmacol. 32:3303-3813. Bandiera, S . ; et a l . (1984) Polychlorinated dibenzofurans (PCDFs): effects of structure on binding to the 2,3,7,8-TCDD cyt oso lic receptor protein, AHH induction and to xi c it y . Toxicology 32:131-144. Bradlaw, J . ; et al . (1979) Induction of enzyme a c t i v i t y in cell culture: a rapid screen for detection of planar polychlorinated organic compounds. J. Assoc. Off. Anal. Chem. 62:904-916. Bradlaw, J.; et a l . (1930) Comparative induction of aryl hydrocarbon hydroxy lase a c t i v i t y in v it ro by analogues of dioenzo-p-dioxin . Cosmet. Toxicol. 13:627-635. Commoner, B.; et a l . (1934, May 1) Environmental and economic analy si s of alternative municipal solid waste disposal technologies. I. An assessment of the r i s k s due to emissions of chiorinated dioxins and dibenzofurans from proposed New York City i n c i n e r a t o r s . Cooper Engineers. (1934) Ai r emissions and performance testing of a dry scrubber (quench reactor) dry Venturi and fabric f i l t e r system operating on flue gas from combusion of municipal solid waste at Tsushima, Japan. Czuwa, J.M.; Hites, R. (1934) Environmental fate of ccmbustion-generated poly chlorinated dioxins and furans. Environ. Sci . Technol . 16:444-450. Dencker, L . ; et a l . (1985) Fetal thymus organ culture as an in v i t r o model for the t o x i c i t y of 2 , 3 , 7,8-tetrachlorodibenzo-p-dioxin and i t s congeners. Mol. Pharmacol. 27:133-140. Denison, M.S.; Wilkinson, C.F. (1985) Id e n t i f i c a t io n of the Ah receptor in selected mammalian species and induction of aryl hyrocarbon hydroxylase. Eur. J. Biochem. 14:429-435. Des Rosiers, ?. ( 1934) PC3s, PCDFs, and PCDDs re s ul ti ng from transfomner/ capacitor fi r e s : an overview. Proc. 1933 PCS seminar. Research project 2028, Ele ctr ic Power Research In st it u te . Palo Alto, C a l i fo r n i a . Eadon, G . ; et al . (1982) Comparisons of chemical and bio log ica l data on soot samples from the Binghamton State Office 3uild ing. (Unpublished report). Gasiewicz, T.A.; Rucci, G. (1984) Cytosolic receptor for tetrachlorodioenzop-dioxin. Evidence for a homologous nature among various mammalian species. Mol. Pharmacol. 26:90-98. GENP 010891 18 783702 Gierthy, J. F. ; C-p^ne, D. (1984) Reversible i n h i b i t i o n of in vitro epithelial cell p r o li fe r at io n by 2 , 3 , 7,3-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol . 74":91 -98. Gierthy, J.F.; Crane, D. (1935 ) In vi tro bioassay for d i o x i n - l i k e a c ti v it y based on alterations in epithiTial cell p r o li fe r at io n and morphology. Fundan. Appl. Toxicol. 5:754-759. Grant, D.L. (1977) Proc. 1 2 th annual workshop on pesticide residues analysis. Winnipeg, Canada, p. 251. Grav'itz, N . ; et al . ( 1933 , Nov. 1) Interim guidelines for acceptable exposure levels in office settings contaminated with PCB and PCS combustion product Epidemiological Studies Section, Califo rn ia Department of Health Services. Greenlee, W. F . ; et al . (1935a) Evidence for direct action of tetrachlorodibenzo-p-dioxin on thymus epithelium. Toxicol. Appl. Pharmacol. 79:112120. Greenlee, W. F . ; et a l . (1985b) Toxicology of chlorinated aromatic hydrocar bons in animals and humans: in vit ro approach to toxic mechanisms. Environ. Health Perspect. 6071)9-76. Greig, J.3.; et a l . (1984) Incomplete correlation of 2 , 3 ,7 , 8 - t e t r a c h l o r o d i benzo-p-dioxin hepatotoxicity with Ah phenotype in mice. Toxicol. Appl. Pharmacol. 74: 17-25. Hassoun, E. et al . (1934 ) Teratogenicity of 2 , 3 , 7,3-tetrachlorodibenzofuran in the mouse. J. Toxicol. Environ. Health 14:337-351. Knutson, J.; Poland, A. (1930) Keratinization of mouse teratoma cell line XB produced by 2 ,3 , 7 , 8 - tetrachlorodibenzo-p-dioxin: an in v i t r o model of to x ic ity . Cell 22:27-36. Kociba, R.J.; Cabey, 0. (1985) Comparative t o x i c i t y and bio log ic a c t i v i t y of chlorinated dibenzo-p-dioxins and furans relative to 2 ,3 , 7,3-tetrachlorodibenzo-p-dioxin (TCDD). Chemosphere 14:649-660. Lamparski, L.L.; et al . (1984) Presence of chiorodibenzo-p-dioxins in a sealed 1933 sample of dried municiDal sewage sludge. Chemosphere 13:361365. Madhukar, B.V.; et a l . (1984) Effects of in vivo administered 2 , 3 , 7 , 8 -tetrachlorodibenzo-p-dioxin on receptor bindTng of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster. Proc. Natl. Acad. S c i . USA 81:7407-7411. McKinney, J.; McConnell, E. (1982) Structural s p e c i f i c i t y and the dioxin receptor. Perg. Ser. Environ. Sci. 5:367-331. GENP 010892 19 783703 Moore, J.A.; et al_. ( 1979) Comparative t o x i c i t y of three haloge.nated dibenzofurans in guinea pigs, mice, and rhesus monkeys. Ann. N.Y. Acad. S c i . 320: 151-1637 Murray, F.J.; et al . ( 1979) Three-generation reproduction study of rats given 2 , 3 , 7,3-tetrachlorodibenzo-p-dioxin in the diet. Toxicol. Appl. Pharmacol. 50:241-252. Nagayama, J.; et al . (1985a) Inducing potency of aryl hydrocarbon hydroxylase in human lymphoblastoid c e l l s and mice by polychlorinated dibenzofurans Environ. Health Perspect. 59:107-112. Nagayama, J.; et a l . (1985b) Genetically mediated induction of aryl hydrocar bon hydroxylase a c t i v i t y in human 1 ymphoplastoid c e l l s by polychlorinated dibenzofuran isomers and 2,3,7,3 - tetrachlorodibenzo-p-dioxin. Arch. Toxicol . 55:230-235. Neal, R.A.; et al . ( 1932 ) The tox ic okinetics of 2, 3 ,7 , 8 -tetrachlorodibenzo-pdioxin in mammalian systems. Drug Metab. Rev. 13:355-285. Neal, R.A. (1985 ) Mechanisms of the biological effects of PC3s , polychlor ina- ted diben zo -p- diox ins, and polychlorinated dibenzofurans in experimental animals. Environ. Health Perspect. 60:41-46. Okey, A.B.; Vella, L.M. (1984) Elevated binding of 2 , 3 , 7,3-tetrachl oro-d ibe.nzo-p-dioxin and 3-methylcholanthrene to the Ah receptor in hepatic cytosols from phenobarbital-treated rats and mice. 3iochem. Pharmacol. 33:531-533. Okey, A.B.; et al . ( 1984 ) Ah receptor in primate l i v e r : binding of 2,3,7,8tetrachlorodibenzo-p-dioxin and carcinogenic aromatic hydrocarbons. Can. J. Physiol. Pharmacol. 62:1292-1295. 01 ie, K . ; et a l . (1933) Formation and fate of PCDD and PCDF from combustion processes. Chemosphere 12:627-636. Ontario Government. (1982, Dec. 16) Chlorinated diox ins and chlorinated dibenzofurans. Ambient a i r guideline. Health Studies Service, Min is tr y of Labour. Ontario Government. (1984, Dec.) S c i e n t i f i c c r i t e r i a document for standard development. Polychlorinated dibenzo-p-dioxins (PCDQs) and polychlorinated dibenzofurans (PCDFs). Min is tr y of the Environment. No. 4-84. December. Poland, A.; et a l . (1979) Mechanism of action of dioxins. Ann. N.Y. Acad. Sci. 320:214-230. Poland, A.; Knutson, J. C. (1982) 2 , 3 , 7 , 8 -Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: an examination of the mechanism of t o x i c i t y . Annu. Rev. Pharmacol. Toxicol. 22:517-554. GENP 010893 20 783704 Poland, A.; et al . ( 1985) Studies on the mechanism of action of halogenated aromatic hydrocarbons. Clin. Physiol. Biochem. 3:147-155. Rappe, C. (1984) Analysis of polychlorinated dioxins and furans. Environ. Sci . Technol. 18:78A-90A. Ri zzardini, M.; et a l . (1983) Toxicological evaluation of urban waste incinera tor emissions. Chemosphere 12:559-564. Safe, S.; et a l . (1985) Polychlorinated dibenzofurans: quantitative structurea c t iv i t y relationships. Chemosphere 14:675-684. Sawyer, T . ; et a l . (1983) Bioanalysis of polychlorinated dibenzofuran and dibenzo-p-dioxin mixtures in f l y ash. Chemosphere 12:529-534. Schwetz , B.A.; et al . ( 1973) Toxicity of chlorinated dibe nzo -p- dio xins. Environ. Health Perspect. 5:87-39. Swiss Government (Bundesamt fur Umweltschutz, Bern). ( 1932 ) Environmental p o l lution due to dioxins and furans from chemical rubbish incineration plants. Schriftenreighe Umweltschutz. No. 5. m Tong, H.Y.; et a l . (1984) Id e n ti fi c a ti o n of organic compounds obtained from incineration of municipal waste by HPLC and GC/MS. J. Chromatogr. 285: 423-441. U.S. Department of Health and Human Services. (1983, Apr. 29) Levels of con cern foh hexa- (HCDD), hepta- (HpCDD) and octachlorodi&enzo-p-dioxins (OCDD) in chickens and eggs. Memorandum. U.S. Environmental Protection Agency. (1931, Nov. 19) Interim evaluation of health r i s k s associated with emissions of tetrachlorinated dioxins from municipal waste resource recovery f a c i l i t i e s . Office of the Administrator. U.S. Environmental Protection Agency. (1982) PCB disposal by thermal destruc tion. National Technical Information Service, S p r i n g f ie l d , VA. P8 32-241860. U.S. Environmental Protection Agency. (1984a, Feb.) Ambient water quality criteria for 2,3,7,8-tetrachlorodibenzo-p-dioxin. EPA-440/5-34-007. U.S. Environmental Protection Agency. (1984b,) Health assessment document for polychlorinated dibenzo-p-dioxins. EPA-600/8-84-014F. U.S. Environmental Protection Agency. (1984c, June) Assessment of emissions of specific compounds from a resource recovery municipal refuse incinerator. Office of Toxic Substances. EPA-560/5-84-002. U.S. Environmental Protection Agency. (1984d, Dec.) Thermal degradation products from d ie l e c t r i c f l u i d s . EPA-560/5-84-009. 21 783705 U.S. Envi ronmentaLProtection Agency. ( 1985, Jan. 9 Proposed guidelines for health ris k assessment of chemical mixtures and request for comments: notice. ~ Federal Register 50:1170-1176. Vickers, A.E.M.; et a l . (1985) Mechanism of action of toxic halogenated aromatics. Environ. Health Perspect. 59:121-129. Weber, H.; et a l . ( 1984) Teratogenicity of 2 , 3 , 7 , 8 tetrachlorodi benzofuran (TCDF) in mice. Toxicol. Lett. 20:183-188. GENP 010895 22 783706 , r* s TABLE 1. SOME APPROACHES TO ESTIMATING RELATIVE TOXIC ITIES OF PCDDs ANO PCDFs Basis/ compound (Basis) K) U> O tti Mono thru di tri 2378-TCDD other TCDDs 2378-PeCDDs other PeCDDs 2378-HxCDDs other HxCDDs 2378-HpCDDs other HpCDDs ocon Sw1ssa Grantb 01 iec Commoner^ New York Statee Ontario^ F0A9 CAh Enzyme LD50 Various effects Vari ous effects 0 0 1 0.01 0.1 0.1 0.1 0.1 0.01 0.01 0 0 0 1 0 0.1 0 0.1 0 0.01 0 0 0 0 1 0 1 0 0.03 0 0 0 0 0 1 1 0.01 1 0.01 1 0.01 1 0.01 0 0 0 1 0 0 0 0.02 0.02 0.005 0.005 <0.00001 0 0 1 0 1 0 1 0 1 0 1 EPA' 1981 0 0 1 1 0 0 0 0 0 0 0 EPA ( current recommend. > .1 Various effects 0 0 1. 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0 o aSwiss Government, 1982. -- i bGrant, 1977. O CO C0 1 le et a l ., 1983. vo Os ^Commoner et a l. , 1984. eFadon et al., 1982. ^Ontario, 1982. 9U.S. OHMS, 1983. bGravitz et al ., 1983 . IJ.S. EPA, 1981. (continued on the following paye) 783707 .c GENP 010897 Basis/ compound Swiss3 Grant*5 01i ec Commoner^ New York Statee (Basis) 2378-TCDFs other TCDFs 2378-PeCDFs other PeCDFs 2378-HxCDFs other HxCDFs 2378-HpCDFs other HpCDFs 0COF Enzyme 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0 0 0.1 0 0.1 0 0.1 0 0.01 0 0 ld50 0.33 0 0.33 0 0.01 0 0 0 0 * 4 TABLE 1. (continued) Ontario^ FDA9 Various effects Various effects 0.02 0.0002 0.02 0.0002 0.02 0.0002 0.02 0.0002 0 0 0 0 0 0 0 0 0 0 i EPA EPA1 current CA^1 1981 recommend. Various effects 1 0 0.1 0 0 0.001 1 0 0.1 0 0 0.001 1 0 0.01 0 0 0.0001 1 0 0.001 0 0 0.00001 0 00 * TAULE 2. POTENCIES OE D I OXI NS ELATIVE TO 2 . 3 . 7 . 8 - T C D O Chemical CODs; Mono th ru t r i 2378-TCDO TCDOs 2378-PeCOD PeCDDs 2378-HxCDOs HxCDDs 2378-HpCDDs HpCDDs 0C DO Guinea pig LO50 <10' 4e 1* .67* .002* .03* -.004* .002* __ m 0o V Carclnogenlcity - lb -- -,04b -- .- -- -- Reproduc 1 1ve/ teratogenic effects ,, Ie .1 < .001k _ " .01c -- _ -- <.00001k Recept or h i n d i ng .001 - . 01e Ie < . 0 1 - . 16e 1 -.05e -- _ -- __ McKinney and McConnell, 1982; Moore et b U.S. EPA. 1984a. c H jrray et a l . , 1979; Schwetz et a l . , 1973; Weber et a l 1904. d Handler* et a l ., 1983. Knutson and Poland, 1900. a l ., 1979. * Oradlaw et a l ., 1979. 9 Oradlaw et a l ., 1900. b llandiera et a l . , 1984.. * liassnun et a l . , 1904. J Cilerthy and Crane, 1985. k Weber et a l .. 1904. Animal cells Enzyme In d u c tio n Alili ER0D Human cel 1s Cell keratIn. 1 Fiat (XH) Cell assay Immun(1 toxlci 1 in vitr. <.001f _ .Ul* ' ^ |e <001-.029 19 I e |J -- <.001- . 01e -- .02-.29 <.0019 .001-.19 <.0019 *.00?-.0049.f -< . 0(l|f <.001* __ .5* -- .005e -- _ -- -. -- __ -- ~ -. .00 |O.P -- .. -- -- -- 1 Poland et a l ., 1979. m Nagayaraa et a l . , 1985a ,b. n Pol and et a l ., 19/1. 0 Dencker et a l . , 1905. P Greenlee et a l . , 1905b. ( t a b l e co n tin u e d on the f o l l o w i n g page.) co CO ow CO a I G E N P 010899 Chente! COFs: Mono th ru t r i 2378-TCDF TCOFs 2378-PeCDF 12467-PeCDF PeCOFs 2378-HxCOFs Hk COFs 2378-HpCDFs HpCOFs Guinea ptg -- .28;.S* -- ,017a -- ,, Carcino genicity -- --- -- -- _ -- _ Reprodur11ve/ teratogenic effects TABLE 2(contInued) Receptor binding En2ymc Induction AIIH ER00 Animal cells Human cells Cell keratin. Flat (XH) cel1 aisay Immuno- toxlctty in TTtro -- . 3 - . 13 * -- -- _ -- -,, < . 0 0 l - . 0 2 * l . h <.00id <.00ld .3;.24h;.4 . 0 1 - . 4f .h.n .4m .001 -,0 5 *1.e <^.0Uld; .04* . 4TM . I 3 d ; . 7 e ; . 6 h <. 3*1 ;. 4m .B" .151 .001-.1*1.e ,IMJ2h <.001-2*1 .n.m -.6TM .04-.5c,h .OOie.h .l)`j - . 2 h .m .001'; .002* .9 -- -c.OOl* .0049 < . 1f -" -- .1* <.005d .1^ <.00lh .00lh . 1 - . 5h .0061 -- OOie .OSe -- -- __ -- _ --** -- .U -- -- -- -.-- -- .10, IP -- -- -- -- -- TABLE 3. CDD/COF ISOMERS OF MOST TOXIC C O N C E R N Isomer Dioxin TEF t Di benzofuran Isomer TEF 2,3,7,8-TCDD 1,2,3,7,8-PeCDO 1,2,3,-4,7,8 -HxCDD 1 , 2 , 3 , 7 ,8,9-HxCDD 1 ,2,3,6 , 7 ,8 -HxCDD 1,2,3,4,6,7,8-HpCDO 1 0.5 0.04 0.04 0.04 0.001 2, 3 ,7 ,8 -TCDF 1, 2 ,3 ,7 ,8 -PeCOF 2 , 3 ,4 ,7 ,8 -PeCDF 1,2,3,4,7,8-HxCDF 1,2,3,7,8,9-HxCDF 1 , 2 , 3 , 5 , 7 ,8 -HxCOF 2,3,4,6,7,8-HxCDF 1,2,3,4,6,7,8-HpCDF 1,2,3,4,7,8,9-HpCDF 0.1 0.1 0.1 0.01 0.01 0.01 0.01 0.001 0.001 a In each homologous group, the rel at iv e t o x i c i ty factor for the isomers not li st e d above is 1 / 1 0 0 of the value li s t e d above. b TEF = Toxicity Equivalence Factor = relative t o x i c i t y assigned. 783711 27 G E N P 010900 TARLE 4. PCDDs/PCOFs IN SOME ENVIRONMENTAL SAMPLES G E N P 010901 Isomer TCDDs PeCDDs HxCDDs HpCDDS OCDO TCDFs PeCDFs HxCDFs HpCDFs OCDF Ai r p a r t i e s . St. Louise CDO/F TCDD TEF cone. eqts. (ppb) 1 0.5 0.04 0.001 0 0.1 0.1 0.01 0.001 0 0.2 1 1.2 25 170 ------ 0.2 0.5 0.048 0.025 ----- --- MSW ESP dust0 CDO/F cone. TCDD eqts. (ppb) 55 10 5 160 6.4 120 0 .12 260 -40 4 80 8 280 2 . 8 160 0.16 40 -- Lake sediment0 CDO/F TCDD cone. eqts. (ppb) 0 0.1 0.34 0 0.05 0.014 0.5 0 . 0 0 1 1.3 -- 0.13 0.013 0.14 0.38 0.014 0.004 1.13 0.14 0.001 -- 1982 Mi 1organi te^ CDD/F cone. TCDD eqts. (ppt) 206 206 -- -- 2768 110.7 7600 7.6 60000 -- -- -- -- -- -- -- -- -- -- MSW f l y ashf Ontario Oslo CDD/F TCDD cone. eqts. .1 (jjpt) CDD/F TCDf cone. eqt! (PP t ) 541 541 ND 467 234 11 5. 591 24 51 2 434 0.43 119 0 .' 467 186 -- Total TCDD eqts. 0.08 32 0.10 324 799 7.: aU.S. EPA . 1984d. "Cooper Engineers, 1904 . cRanpe, 1984. `Mainparski et al ., 1984. '-Czuwa and Hites, 1984. fTong et a l ., 1984. 90es Rosiers, 1984. (continued on th following pagi TABLE 4. (continued) Thermal degradation prods, from d ie l e c tr i c f l u dsa Run Run 8 -13-40 8-30-61 ASKL CDD/F TCDD CDD/F TCDD Isomer TEF cone. eqts. cone. eqts. TCDDs 2378 other PeCOOs 2378 other HxCDOs 2378 other HpCDOS 2378 other OCDD ____ 1m )_____ (u9) 1 0.01 0 0.5 0.002 0 0.04 0 0.0004 0.001 0.00001 0 0 0 00 00 00 0 330 0 37 0 0 0 0.33 0 Jap. MSWb Commercial CPs Soot from PCB f i re9 -- i-- ri---------- Pt. A TEF Pt. B TEF 246TCPC PCPC CDD/F TCDD. cone. eqts. CDD/F TCDD cone. eqts. [lb/MMBTU(xl0-6)] CDD/F TCDD CDD/F TCDD cone. eqts. cone. eqts. (ppm) (ppm) CDD/F TCDD cone, eqts (PP") 0.1 0.1 0.07 0.035 0.04 0.002 0.02 0.01 <0 . 0 0 1 0 0.58 0.58 <0 . 1 0.47 0.24 <0 . 1 0.36 0.014 <1 0.08 <0 . 0 0 1 0.04 0 <1 <1 -- <0 . 1 -- -- <0 . 1 -- -- 2.5 0 . 1 -- 175 -- 500 0.18 -- 0.6 0.6 0.6 0.0 2.5 1.2! 2.5 0.0 1 . 1 0 .0 ' 3.6 0 30 40 2 (continued on the following page) 783713 G E N P 010902 .L TABLE 4. (continued) Isomer TCDFs 2378 other PeCDFs 2378 other HxCDFs 2378 other HpCDFS 2378 other OCDF Thermal degradation prods, from d ie l e c tr i c f l u i d s 3 Run Run 8-13-40 8-30-61 ASKL CDD/F TC00 CDD/F TCDD TEF cone . eqts. cone. eqts. (n9 ) (ug) 0.1 690 0.001 0.1 43 0.001 0.01 7 0.0001 0.001 0 0.00001 00 69 1400 140 4.3 6400 640 0.07 910 9.1 0 29 0.029 0 3.4 0 dap. MSW& Pt. A TEF Pt. B TEF CDD/F TCDD CDD/F TCDD cone. eqts. cone. eqts. [1b/MMBTU( 10"6)] Commercial CPs Soot from PCB fireQ "1 T~ 246TCPC PCPC CDD/F TCDD CDD/F TCDD CDD/F TCDD cone. eqts. cone. eqts. cone. eqts. (ppm ) (ppm) (ppm) 1.31 0.131 0.38 0.038 0.06 0.006 0.01 <.001 0.004 0 1.25 0.125 1.5 0.15 <0.1 -- 12 1.2 16 0.01 0.46 0.046 17.5 1.75 <0.1 -- 358 35.8 312 0.3 0.06 0.006 36 3.6 <0.3 670 6.7 295 0.03 0.02 0.01 <.001 4.8 0 <1 0.005 19 -- 25 0.019 -- 285 172 40 0.29 0 -- Total TCDD eqts 73 789 0.3 1.02 5. 5 0.3 46 .r TABLE 5. USE OF THE TEF APPROACH Isomer PCB fir e soota MSW fly as hb i Sample 1 Sample 2 -- 7 7 --------- CDD/F TCDD eqts. CDD/F TCDD eqts. CDD/F TCDD eqts. cone. (ppm) cone. (ppb) cone. (PPb) Propn. (ppm) (pph) (ppb) TEF factor AC RC CC AC BC AC BC Total TCOOs 2378 TCOOs other TCOOs Total PeCDDs 2378 PeCDDs other PeCDDs Total HxCDDs 2378 HxCDDs other HxCDDs Total HpCDDs 2378 HpCDDs other HpCDDs 1 1 0.01 0.5 0.5 0.005 0.04 0.04 0.0004 000...000 000 011 01 1 0.05 0.95 1 0.07 0.93 1 0.3 0.7 1 0.5 0.5 1.2 1.2 1.2 5.0 5.0 5.0 4.7 4.7 4.7 7 7 7 1.2 0.2 --d 0.6 -- 85 85 2.7 2.7 85 4.3 2.7 0.1 85 0 . 8 2.7 -- 2.5 213 107 0 . 2 1.3 213 7.0 -- -- 213 1.0 6 . 6 3.3 6.6 0.2 6.6 -- 0.2 354 14.2 11.6 0.5 0 . 1 -- 354 4.3 1 1 . 6 0.1 -- -- 354 0.1 11.6 -- -- 184 184 0 . 2 0.1 5.7 _5.7 -- ~-- 184 -- 5.7 "" a Des Rosiers, 1984, assuming only homologue-specific concentrations are known (for isomer-specif1 c analyses; see Table IV). b Sawyer et a l ., 1983. c A = estimated assuming 2378-isomers constitute 1001 of a homologous group. B = estimated assuming occurrence of a ll isomers in a homologous group is equally probable (thus using the ~CC"DO4 proportionality factor in column three). C = estimated by u t i l i z i n g i soiner-spec i f i c analyses (see Table IV). d Values rounding off to less than 0 . 1 are omitted. cn (continued on the following page) TABLE 5. (continued) Isomer PCB fir e soota MSW fly ashh i Sample 1 Sample ? i .1 CDD/F TCDD eqts. CC/F TCDD eqts. CCD/F TCDD eqts. cone. (ppm) cone. (pph) cone. (pph) Propn. (ppm) (pph) (pph) TEF factor AC Bc Cc AC BC AC BC Total TCDFs 2378 TCDFs other TCDFs 000...10101 1 0.03 0.97 28 28 28 Ui Total PeCDFs 2378 PeCDFs other PeCDFs 000...01101 1 0.07 0.93 670 670 670 Total HxCDFs 2378 HxCDFs other HxCDFs 0.01 0.01 0.0001 1 965 0.25 965 0.75 965 Total HpCDFs 2378 HpCDFs other HpCDFs 00..000011 0.00001 1 0.50 0.50 460 460 460 Total TCDD equivalents (TEF) : ItE estimate: . . AHH bioassay: EROD bioassay: Receptor binding assay: Acute to x ic ity bioassay : 783716 2.8 67 9.7 0.5 0.1 1 . 2 -- -- 4.7 35.8 0 . 6 0.3 02..14 6.7 -- 0 . 2 0.3 -- -- 209 209 209 549 549 549 1082 1082 1082 499 499 499 B4 9 46 -- -- - -- -- -- -- -- -- 58 "-- ft 20.9 0.6 0.2 54.9 3.8 0.5 10.8 02..17 0.5 0.2 -- 7.0 7.0 7.0 17.8 17.8 17.8 32.1 32.1 32.1 10.9 10.9 10.9 0.7 --- 1 . 8 0.1 -- H. 3 0.1 -- ___ -- -- 294 26 4 5 32 ""-- 91 -- -- -- -4 -- (continued on the following page) 060I0 cLH3C> ** Table 5. (continued) MSW f l y ash0 Sample 3 Sample 4 Isomer TCDD eqts. (ppb) Propn. CDD/F TEF factor cone. Ac Bc (ppb) CDD/F cone. (ppb) TCDD eqts (ppb) Ac Bc Total TCDDs 2378 TCDDs other TCDDs 1 I 0.01 1 0.05 0.95 12.9 12.9 12.9 12.9 0.6 0.1 2.4 2.4 2.4 0 . 1 2.4 -- Total PeCDDs 2378 PeCDDs other PeCDDs Total HxCDDs 2378 HxCDDs other HxCDDs 0.5 0.5 0.005 0.04 0.04 0.0004 1 0.07 0.93 1 0.3 0.7 37.5 37.5 37.5 75 75 75 18.8 3 1.3 0.2 0.9 -- 7.9 4.0 7.9 0.3 7.9 -- 9.7 0.4 m 9.7 0 . 1 9.7 -- Total HpCDDs 2378 HpCDDs other HpCDDs 0.001 0.001 0.00001 1 0.5 0.5 41.9 41.9 41.9 9.1 -- 9.1 -- 9.1 --- Total TCDFs 2378 TCDFs other TCDFs 0.1 0.1 0.001 1 0.03 0.97 8.2 8.2 3.2 0.8 -- -- 4.4 0.4 4.4 _ _ 4.4 -- Total PeCOFs 2378 PeCDFs other PeCDFs Total HxCDFs 2373 HxCDFs other HxCDFs 0.1 0.1 0.001 0.01 0.01 0.0001 1 0.07 0.93 1 0.25 0.75 19.8 19.8 19.8 38.7 38.7 38.7 2.0 0.1 -- 0.4 0.1 -- 21.0 21.0 21.0 21.6 21.6 21.5 2.1 0.2 0.1 -- 0.1 -- Total HpCDFs 2378 HpCDFs other HpCDFs 0.001 0.001 0.00001 1 0.50 0.50 20.6 20.6 20.6 ___ -- Total TCDD equivalents (TEF): TEF estimate: AHH bioassay: EROD bioassay: Receptor binding assay: Acute t o x ic ity bioassay 38 2 4 _. 5-- 65 -- - -- 16.5 16.6 16.6 9 2 2 11 -- -- 0.7 -- 33 GENP 010906 783717 TABLE 6. EXAMPLE OF A C A LCULATION OF TCDO EQUIVALENTS WHERE ISOMER-SPECIFIC CONCENTRATIONS ARE AVAILABLE Isomer 2 , 3 , 7,8-TCDD Other TCDDs 1 ,2 ,3 ,7 ,8 -PeCDD 1,2,3,6,7,3-HxCQD 1 ,2 ,3 ,7 ,8 ,9-MxCDO 1 ,2 , 3 , 4 , 7,8-HxCDO Other HxCDDs 2 , 3 , 7,8-TCDF 1 ,2 ,3 ,7 ,8 -PeCDF 2 ,3 ,4 ,7,8-PeCDF 1 ,2 ,3 ,6 ,7,8-HxCOF 1,2,3,7,8,9-HxCDF 1 ,2 ,3 ,4 ,7,8-HxCOF 2 ,3 ,4 ,6 , 7,3-HxCDF Other HxCDFs Concentration (PPb) 0.5 20 0.10 0.05 0.5 0.1 50 10.5 0.1 0.01 0.01 0.01 0.01 0.01 1 Relative potency TCDO equivalents (ppb) to o 1 0.01 0.04 0.04 0.04 0.004 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.001 Total 0.5 0.2 0.05 0.002 0.02 0 .0 0 A 0.02 1.05 0.01 0.01 0.001 0.001 0.001 0.001 0.001 1.8 GH]Vp 010907 34 783718 Homo!ogue TCDOs PeCDOs HxCDOs TCQFs PeCDFs HxCDFs _ TA3LE 7. CALCULATION OF TCDD E Q UI VALENTS WHERE ONLY H O M O L O G U E -SPEC IF IC A N AL Y S ES ARE AVAILABLE Concentration (ppb) 0.5 0.5 13 100 150 10 Relat ive potency 1 0.5 0.04 0.1 0.1 0.1 Total TCDO equiv alents (ppb) 0.5 0.25 0.42 10.0 15.0 10.0 36.0 35 GENP 010908 783719 APPENDIX A NOMENCLATURE The following terminology and abbreviations are used in t h is document: 1. The term "congener" refers to any one p a rtic u la r member of the same chemical family; e.g., there are 75 congeners of chlorinated d ib enzo-p -dioxins. 2. The term "homologue" refers to a group of s t r u c t u r a lly related chem ic a ls that have the same degree of chlorin ation. For example, there are eight homologues of CCDs, monochlorinated through octochlorinated. 3. The term "isomer" refers to substances that belong to the same homol ogous class. For example, there are 22 isomers that constitute the homologues ,, of TCDDs. 4. A sp e c ific congener is denoted by unique chemical notation. For example, 2,4,8,9-tetrachlorodibenzofuran is referred to as 2 , 4 ,8,9-TCQF. 5. Notation for homologous classes is as follows: Dibenzo-p-dioxin 0 Dibenzofuran F No. of halooens Acronym Examole 1 through 8 M D Tr T Pe Hx Hp 0 CDDs and CDFs 2,4-DCDD 1 ,4 ,7 ,9-TCDD 6 . Dibenzo-p-dioxins and dibenzofurans that are chlorinated at the 2,3,7, and 8 position s are denoted as "2378" congeners, except when 2,3,7,8-TCDD uniquely referred to; e.g., 1 ,2 ,3 ,7 ,8 -PeCDF and 2,3,4,7,8-PeCDF are both referred to as "2378-PeCDFs." G E N P 010909 A-l 783720 APPENOIX 3 COMPARISON OF DIFFERENT APPROACHES TO CALCULATING 2378-TCQD EQUIVALENTS Table I I I l i s t s a number of d i f f e r e n t approaches to c a l c u l a t i n g 2378TCDD t o x i c i t y e q u i v a l e n t s . Five of the approaches (those that deal with im p o sition 2373-substituted congeners, but not the 3 -p o sitio n substituted con geners) were ap plied to 1. The data in Table IV. 2. Some of the data included in Table I of the Report of the C i t i z e n s A d v i s o ry Committee on Resource Recovery in Brooklyn (March, 1935), produced by Ketcham and the Mt. Si n a i School of Medicine. A summary comparison of the r e l a t i v e r e s u l t s i s found in Table B - l , with the su p p or ti n g ta b l e s attached. (Note that the u n i t s of mass emission are not the same f o r a l l of the f a c i l i t i e s . Th e re fo re , comparison of abso lute numbers between f a c i l i t i e s may be i n v a l i d . ) These data i n d i c a t e th a t , in ge n e r a l, the methods used by the Swiss government, New York S t a t e , and the U.S. EPA (the 1981 approach and the 1935 p r o p o sa l ) all generate r e s u l t s which are w it h in an orde r of magnitude of each other. This suggests th at, w ithin the range considered, the r e s u l t s are not p a r t i c u l a r l y s e n s it iv e functions of the TEFs selected. The procedure recommended by the s t a t e of C a l i f o r n i a , however, g iv e s r e s u l t s which are roug hly an order of magnitude hi g h e r than those generated by the other approaches. In general, the gr eater the c o n t r i b u t i o n from the TCDDs, the greater the s i m i l a r i t y in the r e s u l t s of the methods. This i s due to the f a c t that a l l methods a s s i g n a TEF of 1 f o r 2,3,7,8-TCDD (and 1 to a ll TCDDs, when i s o m e r - s p e c i f i c ana lyses are not a v a i l a b l e ) . Because h ig h e r c h l o r i n a t e d GENP 010910 B-l 783721 CDOs and CDFs- c o n t r ib u t e s i g n i f i c a n t l y to the t o t a l , the d i s p a r i t y i s greater between the CA r e s u l t s and those produced by the o t h e r methods, s inc e CA assumes that a l l 2 3 7 8 - s u b s t i t J t e d CDDs/CDFs are as potent as 2 ,3,7,8-TCDO. The othei methods acknowledge, to one degree or another, the reduced t o x i c i t y in hig he r c h lo r in a t e d s p e c i e s ; c f . Table 2. GENP 010911 8-2 783722 TABLE 3-1. RELATIVE 2378-TCOO EQUIVALENTS^ Source EPA *85 EPA *81 Swiss NY CA St. Louis air part. PCB fir e soot ( isomer-speci fic) MSW ESP dust Lake sediment Mi 1organite Oslo MSW flyash Ontario MSW flyash Jap. plant A Jap. plant B A1 bany Wright-Pat. (best) Wright-Pat. (worst) 1 1 1 1 1 1 1 1 1 1 1 1 0.3 0.03 0.2 -- 0.6 -- 0.8 0.3 0.6 0.3 0.2 0.4 1 2 40 4 3 30 3 2 30 2 2 30 2 0.9 30 1 2 20 1 23 1 27 0.8 2 3 0.4 2 5 2 3 20 2 2 20 ^Calculated using the Toxicity Equivalence Factors shown in Table 1. GENP 010912 B-3 783723 16010 d N 3 0 TABLE B-2. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR ST. LOUIS AIR PARTICULATES USING HOMOLOGUE-SPECIFIC DATA Compound Mono to t r i CDD/F cone. (PPb ) X 2378-TCDD TCDOs 0.2 0 2378-PeCDD PeCDDs 1 0 2378-HxCDO HxCDDs 1.2 0 2378-HpCDD HpCDDs 25 0 OCDD 170 EPA 1985 TEFs its (PPb ) 00 EPA 1981 TEFs TEs tppb) 00 1 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0.2 0 0.5 0 0.048 0 0.025 0 1 1 0 0 0 0 0 0 0.2 0 0 0 0 0 0 0 0 00 0 Swi tzerland TEFs TEs (PPh) 00 1 0.01 0.2 0 0.1 0.1 0.1 0 0.1 0.1 0.01 0.01 0.12 0 0.25 0 00 New York TEFs TEs (ppb) 00 1 0.2 00 1 0 0.03 0 1 0 0.036 0 00 00 00 Cali forn i a TEFs TEs 1 (ppb) 0 ,1 0*1i 1 0.2 00 11 00 1 1.2 00 1 25 00 00 Mono to t r i X 0 2378-TCDF TCDFs NA 0 0.1 0.001 2378-PeCDF PeCDFs NA 0 0.1 0.001 2378-HxCDF HxCOFs NA 0 0.01 0.0001 2378-HpCDF HpCDFs NA 0 0.001 0.00001 OCOF NA 0 Total 2378-TCDD equivalents 0 0 0 0 0 0 0 0 0 0 0.7 0 0 0 0 0 0 0 0 0 0 00 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 00 00 0.2 0 0 0 0 0 0 0 0 0 0 0.7 0 0.33 0 0.33 0 0.01 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.2 0 l 0 1 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 27.4 7R3794 TABLE B-3. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR PCB FIRE SOOT USING ISOMER-SPECIFIC DATA 15 c* * GENP 010914 Compound Hono to tri 2378-TCDD TCODs 2378-PeCDD PeCDDs 2378-HxCDD HxCDDs 2378-HpCDD UtIal HpCODs OCDD CDD/F cone. (ppm) x 0.6 0.6 2.5 2.5 l.l 3.6 3 4 2 EPA 1985 TEFs TE's' (ppm ) 00 EPA 1981 TEFs TEs (ppm) 00 1 0.01 0.6 0.006 1 1 0.6 0.6 0.5 0.005 1.25 0 0.0125 0 0 0 0.04 0.0004 0.044 0 0.00144 0 0 0 0.001 0.00001 0.003 0 0.00004 0 0 0 0. 0 0 0 Switzerland TEFs Tts (ppm) 00 1 0.01 0.6 0.006 0.1 0.25 0.1 0.25 0.1 0.11 0.1 0.36 0.01 0.01 0.03 0.04 00 New York TEFs TEs (ppm) 00 1 0.6 00 1 2.5 00 0.03 0 0.033 0 00 00 00 California TEFs TEs (ppm) 1 00 1' 1 0 0.6 0 1 2.5 00 1 1.1 00 13 00 00 Mono to tri X 0 00 00 0 0 00 0 2378-TCDF TCDFs 12 ___ ,,0.1____ ____1.2____ _ 0 ____ 16 0.001 0.016 0 0 0 -0.-U - - -1.2----- . 0.33 - 3.,96^ - 1 -- 0.1 1.6 0 0 0 --- 12 - 0 2378-PeCDF ... 358 PeCDFs 312 0.1 _ . -35.8-. --.0- - 0.001 0.312 0 - o -----0 0.1 -35.8 31.2 0.33 -- 1.18.1.400 1 - --- 358 00 2378-HxCDF HxCDFs 670 295 0.01 0.0001 6.7 0 0.0295 0 0 0 .1 67 0.01 6.7 1 670 0 0.1 29.5 0 0 0 0 2378-HpCDF HpCDFs 285 172 0.001 0.00001 0.285 0 0.00172 0 0 0.1 28.5 0 0 1 285 00 0 000 0 -v] CDF 40 0 0000 -ONv>li Total 2378- TCDO equivalents 0 46 0 00 0 1.2 196 00 132 00 1332 O m o )-- i O vo t--* U tuI -si 0U0 sen TABLE B-4. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR MSW ESP OUST USING HOMOLOGUE-SPECIFIC DATA AND 2378 TEFs Compound Mono to tri 2378-TCDD TCDDs 2378-PeCDD PeCDDs 2378-HxCDD HxCDDs 2378-HpCDD HpCDDs OCDD CDD/F conc. (ppb ) X 5 10 0 160 0 120 0 260 EPA 1985 TEFs TFs (ppb) 00 1 0.01 5 0 0.5 0.005 5 0 0.04 0.0004 6.4 0 0.001 0.00001 0.12 0 00 EPA 1981 TEFI TEs (PPb) 00 15 10 00 00 00 00 00 00 00 Switzerland TEFs TEs (ppb) 00 l 0.01 5 0 0.1 1 0.1 0 0.1 16 0.1 0 0.01 0.01 1.2 0 00 New York TEFs TEs (ppb) 00 California TEFs TEs (ppb) i 0 0 1 5 ' .1 000 5 0 1 10 1 10 000 0 0.03 0 4.8 0 I 0 160 0 0 0 1 120 000 0 0 00 0 Mono to tri X 0 2378-TCDF 40 ~TCDFs~------ - 0 0.1 .001 2378-PeCOF 80 0.1 PeCDFs b o.ooi 2378-HxCDF HxCDFs 280 0 0.01 0.0001 2378-HpCDF HpCDFs 160 0 0.001 0.00001 OC DF 40 0 Total 2378-TCDD equivalents 0 4 0 8 0 2.8 0 0.16 0 0 31 0 0 0 ,,0 .. 0 0 0 0 0 0 00 0 000 0 0 _ _ .--0.1____ 0 0.1 JL. _ _ ____ 0.33-- -- 13.2- - -- 1 -- ---- 40-0 000 0 0-_- - . 0.1--. -- -0 0 0.1 0 -- 0.33 -26.4 -- 1 - --- 000 80-- 0 0 0.1 28 0 0.1 0 0.01 0 2.8 0 1 0 280 0 0 0.1 16 00 0 00 l 160 00 0 0 00 5 0 000 0 79 62 85b:. TABLE B-5. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR LAKE SEOIMENT USING HOMOLOGUE-SPEC IF IC DATA ENP 010916 Compound Mono to tri 2378-TCDD TCDDs 2378-PeCDD PeCDDs 2378-HxCDD HxCDOs 2378-HpCDD HpCDDs OCOD 1CDD/F cone. (eek)- EPA 1985 tefs TEs (pPb > X0 0 EPA 1981 TEEs TEs (ppb) 00 01 0 0 0.01 0 1 1 0 0 0.1 0.5 0 0.005 0.05 0 0 0 0 0 0.34 0 0.04 0.0004 0.0136 0 00 0 0 0.5 0.001 0.0005 0 0 0.00001 0 0 0 0 1.3 0 00 0 Switzerland TEFs TEs (PPb) 00 1 0.01 0 0 0.1 0.01 0.1 0 0.1 0.034 0.1 0 0.01 0.01 0.005 0 00 New York TEFs TEs (ppb) 00 California TEFs TEs (ppb) 1 00 1 0 1 1 0 0 0 00 1 0.1 1 0.1 0 0 00 0.03 0 0.0102 l 00 0.34 0 0 0 l 0.5 0 0 00 0 0 00 Mono to tri X 0 00 00 0 0 0 00 2378-TCDF 0.13 0.1 0.013 0 0 0.1 0.013 _JCDEs. __ ___ ,0_____ ^0 . 0 0 1 - - 0 ------- ------------ 0---- 0------ -------- - 'OtI ---- ~ 0 " ---- 0.33 0 0.0429 1 U ""0 0.13 O' 2378-PeCDF - rcLUr5 - - 0.14 0.1 n---- u -- -- n=.U. n m 0.014 o' n u----.- U ----------- A ------ - 0n u - ... --- 0.1 nu . i1- --- 0.014 0.33 0.0462 u---f \ -- ---;-- -- -- =^au---- -- -- ------ u 1____ rt u 0,14 A u 2378-HxCOF 0.38 0.01 0.0038 0 0 0.1 0.038 0.01 0.0038 l 0.38 HxCDFs 0 0.0001 0 0 0 0.1 0 % 0 0 00 2378-HpCDF HpCDFs 1.13 0. 0.001 0.00001 0.00113 0 00 0 0.1 0.113 0 0 1 1.13 00 0 0 0 00 OCDF 0.14 0 Total 2378-TCDD equivalents 00 0.1 00 0 00 1.2 00 0.2 0 2.7 TABLE B-6. CALCULATION OF 2373-TCDD TOXICITY EQUIVALENTS FOR MILORGANITE USING HOMOLOGUE -SPECIFIC DATA B 4 GENP 010917 Compound CDD/F cone. (ppt) Mono to tri X 237B-CDD TCDDs 206 0 2378-PeCDD PeCDDs 0 0 237B-HxCD0 HxCDDs 2768 0 2378-HpCDD HpCODs 7600 0 OCOD 60000 EPA 1985 TEFs TEs (ppt) 00 1 0.01 206 0 0.5 0.005 0 0 0.04 0.0004 110.72 0 0.001 0.00001 7.6 0 00 EPA 1981 TETs "TEs (ppt) 00 1 206 10 00 00 00 00 00 00 00 Switzerland TEFs TEs (ppt) 00 1 0.01 206 0 0.1 0 0.1 0 0.1 276.8 0.1 0 0.01 0.01 76 0 00 New York TEFT TS (Ppt) 00 California TEFs TEs (ppt) 1 00 1 206 i Ji 000 206 0 10 1 000 0 0 0.03 0 83.04 0 1 0 2768 0 0 0 1 7600 000 0 000 0 Mono to tri X 0 0 2378-TCDF NA -- TCDFs----- --- --- 0.1 0 0.001' -- -- 0-- 2378-PeCDF NA 0.1 -- PeCUr-s----------0---- Ot OOI" 0 0 2378-HxCDF NA 0.01 0 HxCDFs 0 0.0001 0 2378-HpCDF NA 0 . 0 0 1 0 HpCOFs 0 0.00001 0 OCDF NA 0 0 Total 2378-TCDD equivalents 324 0 0 -- Q. ------ " 0 0 0 0 0 0 0 0 0 0 00 00 00 206 0 0.1 -- o.i 0.1 0.1 0.1 0.1 0.1 0 0 0 0 --- -- o 0 0 0 0 0 0 0 559 00 0.33 0 0 0 0.33 0 0 0 0.01 0 0 0 00 00 00 289 00 10 00 10 00 10 00 10 00 00 10600 1 G E N P 010918 ' TABLE B-7. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR OLSO MSW FLY ASH USING HOMOLOGUE-SPECIFIC DATA 4 Compound Mono to tri 2378-TCDD TCDDs 2378-PeCDl) PeCDOs 2378-HxCDD HxCDDs 2378-HpCDD HpCDDs OCDD CDD/F cone. (PPt) x NA 0 11 0 51 0 119 0 186 EPA 1985 TEFs Its (PPt) EPA 1981 TFFs- ~TFT (ppt) 0 00 0 1 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0 0 5.5 0 2.04 0 0.119 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 Switzerland TtFs TF? (ppt) 00 1 0.01 0 0 0.1 0.1 0.1 0.1 0.01 0.01 1.1 0 5.1 0 1.19 0 00 New TEFs 0 1 0 oL. >- TEs (PP.t) Cali fornia TEFs TEs (ppt) 00 0 0 1 'i 00 0 0 1 0 0.03 0 0 .0 11 0 1.53 0 0 0 1 0 1 0 1 0 11 0 51 0 119 0 000 0 Mono to t r i X0 2378-TCDF TCDFs NA 0 . 1 0 0.001 2378-PeCDF NA 0 . 1 PeCDFs 0 0.001 2378-HxCDF NA 0 . 0 1 HxCDFs 0 0.0001 2378-HpCDF NA 0 . 0 0 1 HpCDFs 0 0.00001 OCUF NA 0 Total 2378-TCD equivalents 0 0 0 0 0 0 0 0 0 0 7.7 0 0 0 0 0 0 0 0 0 0 00 0 0.1 0 0.1 0 0.1 0 . 0.1 0 0.1 0 0.1 0 0.1 00 00 0 0 0 0 0 0 0 0 0 0 0 7.4 0 0.33 0 0.33 0 0.01 0 0 0 0 0 0 0 0 0 0 0 0 0 0 12.5 0 1 0 l 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 181 783729 _ Q fu o >--vol Vo CO Ho1* Compound Mono to tr i 2378-TCDD TCDOs 2378-PeCDD PeCDDs 2378-HxCDD HxCDDs 2378-HpCDD HpCDDs OCDD TABLE B-8. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR ONTARIO MSW FLY ASH USING HOMOLOGUE-SPECIFIC DATA CDD/F cone. (PPt) X 541 0 467 0 591 0 434 0 467 EPA 1985 TFFs~ TE? (PPt) EPA 1981 TtTs- n r ? (PPt) 0 1 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0 541 0 233.5 0 23.64 0 0.434 0 0 1 1 0 0 0 0 0 0 0 541 0 0 0 0 0 0 0 0 00 0 Switzerland TEFs TEs <ppt) 00 1 0.01 541 0 0 . 1 46.7 0.1 0 0 . 1 59.1 0.1 0 0.01 0.01 4.34 0 00 New York TEFs TEs (PPt) 0 1 0 1 0 0.03 0 0 541 0 467 0 17.73 0 00 00 00 Cali fornia TEFs TEs (PPt) i 00 l* 541 00 1 467 00 1 591 00 1 434 00 00 Mono to tri X0 00 2378-TCDF NA 0 . 1 00 TCDFs 0 0.001 00 2378-PeCDF NA 0 . 1 00 PeCDFs 0 0.001 00 2378-HxCDF NA 0 . 0 1 HxCDFs 0 0.0001 0 0 0 0 03 oC0-nO0I 2378-HpCDF HpCDFs NA 0 . 0 0 1 0 0 0.00001 0 0 0 OCDF NA 0 00 Total 2378- TCDD equivalents 799 00 0000 0 0 0.1 0 0.1 0 0.33 0 1 0 00 0 0 0 0 0.1 0 0.1 0 0.33 0 1 0000 0 0 0 0.1 0 0.1 0 0.01 0 1 00 0 0 0 0 0 0.1 00 000 1 00 00 0 0 00 541 ft 0000 0 651 1026 20'* 3 ,r TABL B-9. CALCULATION OF 2378-TCDO TOXICITY EQUIVALENTS FOR MSW AT JAPANESE PLANT A USING HOMOLOGUE-SPECIFIC DATA V'T m? $ r GENP 010920 b-u j , i 783731 Compound Mono to trl 2378-TCDD TCODs 2378-PeCDD PeCDDs 2378-HxCDD HxCDDs 2378-HpCDD HpCDDs OCDD CDD/F EPA 1985 cone.a TF? TEsa CPA 1981 TEFs Tia- X 0.1 0 0.07 0 0.04 0 0.02 0 0.01 0 1 0.01 0.5 0.005 0.04 * 0.0004 0.001 0.00001 0 00 0.1 1 01 0.035 0 0 0 0.0016 0 00 0.00002 0 00 00 0 0.1 0 0 0 0 0 0 0 0 Switzerland TEFs TEsa 0 1 0.01 0.1 0.1 0.1 0.1 0.01 0.01 0 0 0.1 0 0.007 0 0.004 0 ' 0.0002 0 0 New York TEFs- TEsa 00 1 0.1 00 California TEFs TEsa i 00 i-i - 0.1 00 1 0.07 1 0.07 0 f 00 0.03 0 0.0012 1 00 0.04 0 0 0 1 0.02 0 0 00 0 0 00 Mono to trl x 0 2378-TCDF TCDFs 1.31 0 0.1 0.001 2378-PeCDF PeCDFs `0.38 _ 0 . 1 _ __ 0 0.001 2378-HxCDF HxCDFs 0.06 0 0.01 0.0001 2378-HpCDF HpCDFs 0.01 0 0.001 0.00001 CDF 0.004 0 Total 2378-TCDD equivalents 00 0 0.131 0 0 0 0 0 0.030 0 _0____ __ _ 0 00 0.0006 0 00 0 0 0.00001 0 00 0 0 00 0 0.3 0.1 0 0 0 0 00 0.1 0.131 0.33 0.4323 1 1.31_ 0.1 0 0 0 00 -0...L _ ___ 0.038_ ___0.33. ____ 0.1254, ,,,1 _ ____0.38 _ 0.1 0 0 0 00 0.1 0.006 0.01 0.0006 1 0.06 0.1 0 0 0 00 0.1 0.001 0 0 1 0.01 0 0 0 0 00 0 0 0 0 00 0.3* 0.7 2.0 Units = lb/MM BTU(X10-6) A y r) TABLE B-10. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR MSW AT JAPANESE PLANT B USING H O M O L O G U E - S P E C IF IC DATA ? ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 5? O Compound CDD/F EPA 1985 conc.a TEFs TT?a EPA 1981 TEFs TFsa Switzerland TTs Esa New York TEFs TEsa California TCF TEsa Mono to tri 2378-TCDD TCDDs 2378-PeCDD PeCDDs 2378-HxCDD HxCDDs 2378-llpCDD HpCDDs OCDD X0 0.58 " 1 0 0.01 0.47 0 0.5 0.005 0.36 0 0.04 0.0004 0.08 0 0.001 0.00001 0.04 0 00 0.58 0 1 1 0.235 0 0 0 0.0144 0 0 0 0.00008 0 00 00 0 0.58 0 0 0 0 0 0 0 0 0 1 0.01 0.1 0.1 0.1 0.1 0.01 0.01 0 0 0.58 0 0.047 0 0.036 0 .0.0008 0 0 0 1 0 1 0 0.03 0 0 0 0 00 0.58 0 i1 J 0 0.47 0 1 0 0.0108 0 1 0 01 00 00 0 0.58 0 0.47 0 0.36 0 0.08 0 0 783732 Mono to tr i X 0 2378-TCDF TCDFs 1.25 0 0.1 0.001 2378-PeCDF PeCDFs 0.46 0 0.1 0.001 2378-HxCDF HxCDFs 0.06 0 0.01 0.0001 2378-HpCDF HpCDFs 0.02 0 0.001 0.00001 OCDF 0.01 0 Total 2378-TCDD equivalents 0 0.125 0 0.046 0 0.0006 0 0 0 0 0 0 0 0 0.00002 0 0 0 00 1.0 00 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 00 00 % 0.6 0 0.125 0 0.046 0 0.006 0 0.002 0 0 0.8 0 0.33 0 0.33 0 0.01 0 0 0 0 0 0.4125 0 0.1518 0 0.0006 0 0 1 0 1 0 l 0 01 00 00 1.6 0 1.25 0 0.46 0 0.06 0 0.02 0 0 3.3 aUn i t s = lb/MM BTU(X10'6 ) G E N P 0 1 0 9 2 2 B-n 703733 TABLE B - l l . .r CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR MSW AT ALBANY USING HOMOLOGUE-SPECIF IC DATA Compound Mono to tri 2378-TCDD TCDDs 2378-PeCDO PeCDOs 2378-HxCDD HxCODs 2378-HpCDD HpCDDs OCDD CDD/F cone. (ng/m3) X 0.45 14 97 0 53 0 71 0 10 EPA 1985 TEFs TEs (ng/m3) FPA 1981 TEFs TEs~ ( ng/in3) 0 1 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0 0.45 0.14 48.5 0 2.12 0 0.071 0 0 l l 0 0 0 0 0 0 0 0.45 14 0 0 0 0 0 0 0 00 0 Swi tzerland TtFs Its (ng/m3) New York TFFs TEs" (ng/m3) 0 1 0.01 0.1 0.1 0.1 0.1 0.01 0.01 0. 0.45 0.14 9.7 0 5.3 0 0.71 0 0 1 0 1 0 0.03 0 0 0 0 0.45 0 97 0 1.59 0 0 0 0 0 00 Cali fornia ttfs rrr (ng/m3) 1 00 1 -1 0.45 00 1 97 c0 1 53 00 1 71 00 00 Mono to tri X 0 23 78-TCDF TCDFs 2.1 33 0.1 0.001 2378-PeCDF 21 0 . 1 PeCOFs 0 0.001 2378-HxCDF HxCDFs 4 0.01 0 0.0001 2378-HpCDF HpCDFs 1 0.001 0 0.00001 OCDF 20 Total 2378-TCDD equivalents 0 0.21 0.033 2.1 0 0.04 0 0.001 0 0 54 0 0 0 0 0 0 0 0 0 0 00 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.21 3.3 2.1 0 0.4 0 0 0.33 0 0.33 0 0.01 0 0 0.693 0 6.93 0 0.04 0 0 1 0 1 0 1 0 0 2.1 0 21 0 4 0 0 0.1 00 0.1 0 0 1 1 0 0 0 00 00 0 ft 14 2 2 00 107 00 250 TABLE B-12. CALCULATION OF 2378-TCOD TOXICITY EQUIVALENTS FOR VIP AFB (BEST) USING HOMOLOGUE-SPECIFIC OATA Compound Mono to trl 2378-TCDD TCDDs 2378-PeCDD PeCDDs 2378-HxCDD HxCDDs 2378-HpCOD HpCDDs 'OCDD CDD/F cone. (ng/m3 ) EPA 1985 TEFi TEs (ng/m3) EPA 1981 TEFs - TEs~ (ng/m3) X0 00 0 0.4 1 0 0.01 0.4 1 01 0.4 0 0.4 0.5 0 0.006 0.2 0 00 0 0 1 0.04 0 0.0004 0.04 0 0 0 0 0 3 0.001 0.003 0 0 0.00001 0 0 0 0 30 00 0 Switzerland TEFs (ng/m3) 00 1 0.01 0.4 0 0.1 0.04 0.1 0 0.1 0.1 0.1 0 0.01 0.01 - 0.03 0 00 New York TEFs TEs (ng/m3) 00 1 0.4 00 1 0.4 00 0.03 0 0.03 0 00 00 00 California TEFs TEs (ng/in3) i 00 1 0.4 00 1 0.4 00 11 00 l3 00 00 Mono to trl X 0 00 2378-TCOF 8 " TCDFs-----------0-- " 0.1 07001 " ---0~0~.8- 0 ~0---- 2378-PeCDF PCDFs 3 0.1 0 0.001 0.3 0 0 0" 2378-HxCDF HxCDFs 4 0.01 0 0.0001 0.04 0 0 0 2378-HpCDF HpCDFs 9 0.001 0.009 0 0 0.00001 0 0 OCDF 20 00 Total 2378- TCDD equivalents 1.8 0 0 -0 0 0L 0 0 0 0 0 0.4 0 0.1 0.1 -- 0.1 0.1 0.1 0.1 ' 0.1 0 0 k 0 0 0 00 0.8 0.33 2.64 1 8 0 -0 - o ---- -- o-- -----0 -- 0.3 0 0.33 0 0.99 0 1 0 3 - -- - .un 0.4 0.01 0.04 1 000 0 4 0 0.9 0 0 1 9 0 0 0 00 000 00 3.0 4.5 28.8 TABLE B - l 3. CALCULATION OF 2378-TCDD TOXICITY EQUIVALENTS FOR WP AFB (WORST) USING HOMOLOGUE-SPECIFIC DATA Compound CDD/F cone. (ng/m3) Mono to tri X 2378-TCDD TCDDs 4 0 2378-PeCDD PeCDDs 3 0 2378-IIxCDD HxCDOs 6 0 2378-HpCDD HpCDDs 32 0 OCDD 16 EPA 1985 TTFs ITT" (ng/m3) EPA 1981 TTFT" -- r r ? (ng/m3) 0 1 O.Ol 0.5 0.005 0.04 0.0004 0 4 0 1.5 0 0.24 0 0 1 1 0 0 0 0 0 4 0 0 0 0 0 0.001 0.00001 0.032 0 0 0 0 0 0 00 0 Switzerland TtFs TEs (ng/m3) 0 1 0.01 0.1 0.1 0 4 0 0.3 0 0.1 0.1 0.01 0.01 0.6 0 0.32 0 00 New York TEFs TEs (ng/m3) 0 1 0 1 0 0.03 0 0 4 0 3 0 0.18 0 00 00 00 Cali fornia TEFs TEs (ng/m3) 1 00 ([ .i 0 -4 0 13 00 16 00 1 32 00 00 Mono to tr i X0 2378'TCDF TCDFs 31 0 . 1 0 0.001 2378-PeCDF PeCOFs 15 0 . 1 0 0.001 2378-HxCDF 23 0 . 0 1 HxCDFs 0 0.0001 2378-HpCOF 93 0 . 0 0 1 HpCDFs 0 0.00001 OCDF 80 Total 2378-TCDD equivalents 0 3.1 0 1.5 0 0.23 0 0.093 0 0 11.0 0 0 0 0 0 0 0 0 0 0 00 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 0 0.1 00 00 4 0 3.1 0 1.5 0 2.3 0 9.3 0 0 21.4 0 0.33 0 0.33 0 0.01 0 0 0 0 0 10.23 0 4.95 0 0.23 0 0 0 0 22.6 0 1 0 1 0 1 0 1 0 0 0 31 0 15 0 23 0 93 0 0 207