Document rxzaO98oBzJgaBb69jYggaRwr

Sunmary of Presentation to Dioxin Task Force Jefferson City, MO 14 April, 1983 Robert A. Neal r .. w/x ^ \i Bj/ rEf*ts*-iitiV,vc>'r-'1ir --'].-*wIaS -\`ik.a\fi- TO P H O T E C T ^ e ORDER. The purpose of my presentation was to review what is known about the toxicity of 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD) (Slide 1) to experimental animals and man. In regulating human exposure to TCDD, we are fortunate to have considerable information about the toxicity of this compound to humans. Information on human toxicity is generally not available on other compounds of environmental concern. However, in spite of the existence of a substantial data base, there are aspects of TCDD toxicity about which there is still considerable question. I will attempt to address some remarks to these data gaps. 0 ro 0 kJ4 X j & In my presentation I will confine my remarks to those toxic effects in experimental animals and man which are supported by objective and scientifically sound data. As is generally the case with environmental contamination with toxic compounds, there have been numerous "scientific" opinions for the existence or absence of toxic effects as a result of exposure of experimental animals or man to TCDD whicn are not consistent with the existing scientific data. I believe it is essential that we differentiate between those concerns or lack of concern for human health or environmental degradation which are based on scientific fact from those based on speculation. With these distinctions in mind groups such as yours will be in a better position to make informed decisions concerning risks or potential risks resulting from human exposure to these compounds. There have been a number of instances of human poisoning by TCDD. This slide (Slide 2) lists some of the more important ones. First of all there have been a number of accidents in industrial facilities which resulted in exposure of workers to TCDD. Most of these accidents have occurred during the synthesis of 2,4,5-trichlorophenol by alkaline hydrolysis of 2,4,5,6tetrachlorobenzene. On July 10, 1976, an accident occurred in Seveso, Italy, which resulted in the exposure of a substantial nonindustrial population to TCDD. The importance of this particular accident is that it resulted in the first substantial exposure of women, particularly pregnant women, and children to TCDD under conditions in which unequivocal illness occurred. One minor incident resulted in the poisoning of two, or perhaps three, chemists involved in the synthesis of TCDD. The other major incident listed was the poisoning which occurred when used oil, contami nated with TCDD, was used for dust suppression on horse show rings in Missouri, an incident with which you are very familiar. The acute toxicity of TCDD is quite variable depending on the animal species examined (Slide 3). The guinea pig is the most sensitive and the hamster the least sensitive of all the animal species that have so far been examined in detail. The acute toxicity in guinea pigs as compared to hamsters differs by approximately 5000-fold depending on the route of administration. It is frequently stated that TCDD is the most toxic -J- * F chemical known. This is, of course, not true. Botulinum toxin and tetanus toxin are more toxic than TCDD in all species examined. Also, in some species (e.g. the hamster), there are a number of compounds, including some insecticides in commercial use, which are more acutely toxic than TCDD. What is the acute toxicity of TCDD in humans? In spite of a number of incidents of human poisoning, there is no evidence that a human fatality has occurred solely as a result of exposure to TCDD. However, in all of these incidents of accidental exposure, we have no definitive data on the doses to which humans were exposed. The only reasonably accurate doseresponse data for TCDD toxicity in humans comes from studies carried out in Halmesburg Prison in Pennsylvania in the mid-1960's. In these studies, Dr. Albert Kligman of the University of Pennsylvania exposed approximately 60 prisoners to dermal doses of 0.2 to 16 vg of TCDD. These doses were reported to have caused no toxic effects. Subsequently, a similar number of prisoners (approximately 10) were exposed to larger doses, some as high as 7500 pg applied dermally in smaller doses over a period of a few weeks. These doses were reported to cause chloracne. However, no other clinical symptoms were observed in the subjects of these studies. When one considers all of these data, it is reasonable to conclude that humans appear to be one of the less sensitive species to the acute and subacute toxic effects to TCDD. A number of studies have been performed examining the potential for TCDD to cause reproductive toxicity in experimental animals. This slide (Slide 4) shows the minimum dose of TCDD causing reproductive toxicity in various species and in various studies- The data shown here for monkeys ignores the data generated in studies at the University of Wisconsin. There is considerable controversy surrounding the conduct of these studies. In my opinion, we must await replication of these studies by another laboratory. It is important to note that the exposure of male mice (but not females) to high levels of TCOD for extended periods of time does not result in a decrease in reproductive capacity in that sex of that species. These data suggest that TCDD may exert its reproductive toxicity primarily in females. It will be important to examine males of other species to verify that this is the case. There was no evidence of a statistically significant decrease in reproductive efficiency in the populations of women exposed to TCDD in the Seveso incident. I would again like to point to the particular value to toxicology of the data from Seveso. This unfortunate occurrence allows us to assess, although in a limited way, the potential for TCDD to cause reproductive toxicity in human females. TCDD causes teratogenic effects in mice (Slide 5). The dose required is 1-3 ug/kg/day administered during the 7-15th day gestation. Exposure of pregnant rats to certain doses of TCDD causes kidney anomalies in the offspring. There has been considerable debate whether this effect is a true teratogenic effect or, alternatively, the result of the acute toxicity of TCDD to the fetus. In my opinion, the data more strongly supports the -01* effect being the result of TCDD toxicity. To my knowledge no birth defects have been detected in monkeys born to or aborted from TCDD-treated mothers. Also, there was not a statistically significant increase in birth defects in the children born to or aborted from the pregnant women in Seveso who were exposed to TCDD. It was thought initially that an increase in birth defects may have occurred. However, a more careful examination of the data showed an obvious underreporting of birth defects in that region of Italy prior to the accident involving TCDD. When compared to a broader control base, there was not a statistically significant increase in birth defects observed in the exposed group in Seveso. TCDD causes cancer in rats and mice (Slide 6). Tumors have been produced in mice whether the exposure is by way of the diet or applied to the shaved skin on the backs of the animals. The fibrosarcomas produced by dermal application of TCDD to mice is a particularly important observation when viewed in light of the suggestion that soft-tissue tumors i may be increased in human populations exposed to TCDD. A number of studies have been carried out looking for an increase in cancer and, in one study, mortality in humans who have been exposed or potentially exposed to TCDD (Slide 7). A study carried out in Sweden among forestry workers suggested a correlation between exposure to chlorophenols and chlorophenoxy acids and an increase in soft-tissue tumors. Subsequent studies in Finland among forestry workers and in New Zealand among agricultural workers (not shown) similarly exposed to chlorophenols and chlorophenoxy acids failed to show a similar correlation between exposure and soft-tissue tumors. Workers exposed to chlorophenols and chlorophenoxy acids are also potentially exposed to various chlorinated dioxins and in some cases to TCDD. There are a number of confounding factors in the Swedish study which prevent the examination of the existence or absence of a cause-effect relationship between TCDO exposure and soft-tissue tumors in humans. In the first place, the chlorophenols themselves may have been responsible for the increased incidence of cancer. The compound 2,4,6-trichlorophenol is an animal carcinogen. In addition, the forestry workers were also exposed to other comnercial chemicals. These chemicals may have been responsible for the increase in soft-tissue tumors. Finally, an increase in soft-tissue tumors was also observed in forestry workers not known to be exposed to preparations containing TCDD. Thus, the correlation between TCDD exposure and an increase in soft-tissue tumors is questionable at this time. How ever, because of these human data and because dermal exposure of mice to TCDD causes soft-tissue tumors,'further study of this issue is clearly warranted. These studies should be carried out in humans which have developed illness as a result of exposure to TCDD (See Slide 2). An increase in gastrointestinal cancer has been observed in a population of workers poisoned by TCDD in an industrial accident. However, the fact that populations examined was small (about 50 subjects) and an increase in gastrointestinal tumors have not been detected in other TCDD-poisoned populations, raises doubts whether there is a cause-effect relationship between gastrointestinal cancer and TCDD exposure. Finally, a ' population of U. $. workers (121 subjects) poisoned by TCDD in 1949 have been examined for an increase in mortality and various diseases (including cancer). No increases in mortality or morbidity, including incidence of cancer or death, from cancer, was seen in this population. TCDD can cause a number of toxic effects in. experimental animals (Slide 8). In addition to acute lethality, reproductive toxicity and birth defects which have been discussed earlier, TCDD can cause liver damage in some species (rat, mouse), cause a decrease in immunocompetence (mice) and cause an induction of various enzymes in a number of species. The induction of enzymes is not known to have any clinical significance. TCDD also causes a number of toxic effects in humans. These are shown in Slide 9. Of all the symptoms listed, the development of chi oracne is the most frequent and sensitive response of humans to TCDD exposure. A careful examination of all the available data on human toxicity resulting from exposure to TCDD and the closely related compounds, the chlorinated dibenzofurans, strongly suggests that if chloracne is not present, the individual or individuals being examined have not been exposed to a sufficient dose of TCDD to cause other symptoms of toxicity. Often chloracne is the only symptom of TCDD toxicity seen in exposed humans. However, in the more severely exposed populations, liver damage and neurological effects are also seen. Other symptoms such as weight loss, hyperlipidemia, anorexia, hirsutism and loss of libido are also,seen. Another reported manifestation of TCDD toxicity is porphyria cutanea.tarda. However, because this condition .is infrequently seen in humans poisoned by TCDD, it is questionable whether porphyria cutanea tarda is caused by exposure to TCDD. In sumnary, the acute toxicity of TCDD varies widely dependent on the species under examination. The current data indicate that man is one of the least sensitive species to the acute toxic effects of TCDD. The most common and sensitive symptom of TCDD toxicity in humans is chloracne. In more severely poisoned subjects a number of other toxic effects are seen, the most important of which are liver damage and neurological effects. TCDD causes cancer in rats when included in the diet and in mice when included in the diet or applied to'the shaved backs of'this species-; Tfre-" current data do not indicate there has been an increase in cancer in humans exposed to TCDD." However, there is a suggestion that there may be a correlation between soft-tissue tumors in humans and exposure to TCDD. Whether or not there is a cause-effect relationship between soft-tissue tumors and TCDD exposure will require additional studies. 4 1 DR. DONNELL: Our next speaker this afternoon will be 2 Dr. R o b e r t Neal who is the P r e s i d e n t of the C h e m i c a l I n d u s t r y 3 I nstitute of T o x i c o l o g y in the R a l e i g h - D u r h a m , N o r t h Ca r o l i n a 4 area. 5 Dr. Neal is a b i o c h e m i s t , has b e e n a p r o f e s s o r , 6 teacher, r e searcher in the fields of b i o c h e m i s t r y and 7 metabolism for a number of years before joining the Chemical 8 Institute. Some weeks back he came at the invitation of Mr. 9 Robert Feigenbaum to speak to the St. Louis area about the 10 d i o x i n . 11 I t ' s a p l e a s u r e to h a v e h i m b a c k and to h a v e h i m g i v e 12 a m o r e t e c h n i c a l p r e s e n t a t i o n this a f t e r n o o n to the Task F o r c e . 13 Dr. Neal. 14 DR. NEAL: Thank you very much. Perhaps, as Jay 15 Murray did, it might be useful to give a little background on 16 wha t m y e x p e r i e n c e has been with dioxin. 17 C H A I R M A N J U D G E FINCH: P l e a s e do that. 18 DR. NEAL: T h e r e 's been an area of research in m y 19 la b o r a t o r y for about ten years w h i l e I was at V a n d e r b i l t up 20 u ntil about three years ago w h e n I m o v e d to N orth C a r o lina. 21 It was an area of r e s e a r c h , and out of that h ave c o m e 22 a n u m b e r of o r i g i n a l c o n t r i b u t i o n s to the l i t e r a t u r e on the 23 m e t a b o l i s m and m e c h a n i s m s of t o x i c i t y of TCDD. 24 Also involved in the Seveso incident invited over by 25 the Lomba r d i p o l i t i c a l , p e o p l e in p o l i t i c a l p o w e r in the 115 BREDEMAN & ASSOCIATES, INC. i 1 Lombardi region soon after the Seveso incident to consult on 2 that and then was a member of a joint Italian U.S. committee 3 made up of our respective National Academy of Sciences that 4 dealt with this Seveso dioxin issue over a number of years. 5 That com m i t t e e has since b e e n d i s b a n d e d b u t was in e x i s t e n c e 6 for about four years. 7 Involved on an advisory panel of the Environmental 8 Protection Agency on w h a t risk was inherent In use of 2,4,5-T 9 contaminated with dioxin in range land and rice for control of 10 w eeds on those crops. It is a use of 2 , 4 , 5-T that is still 11 r e g i s t e r e d and a u s e for w h i c h is c u r r e n t l y e x i s t e n t . 12 And the job of our s c i e n t i f i c a d v i s o r y p a n e l was to 13 look at the accepted use of 2 , 4 , 5-T contaminated with dioxin to 14 the level of 100 parts per b i l l i o n to m a k e a d e c i s i o n whether 15 there was any immediate or s u b s t a n t i a l h a z a r d to hum a n health 16 as a r e sult of use of t h a t p r o d u c t for c o n t r o l of m e s q u i t e on 17 range land and weeds in rice. So that I've had a fairly 18 s u b s t a n t i a l r e g u l a t o r y and r e s e a r c h i n v o l v e m e n t w i t h this 19 interesting c o m p o u n d 20 So I think with that sort of background let me 21 p r o c e e d then to g i v e s o m e i n f o r m a t i o n a b o u t the a n i m a l and 22 human toxicity of T C D D . Most of what I intended to say has 23 b e e n said a l r e a d y by two p r e v i o u s s p e a k e r s . 24 So I 'll on l y a m p l i f y t h o s e s e c t i o n s of m y 25 presentation which I think m a y give a siightly d i fferent ______________________________ 116_____________________________________________ BREDEMAN & ASSOCIATES, INC. * 1 perspective than was presented by the two previous presenters 2 and spend less time on repeating data that they have presented 3 themselves previously. 4 I think one of the fortunate aspects of TCDD is that -5 we do have a s u b s t a n t i a l a m o u n t of i n f o r m a t i o n a b o u t the h u m a n 6 toxicity of this compound. It is a luxury that's not usually 7 afforded us on other compounds of environmental interest with 8 which we have to deal. 9 There are, of c o u r s e -- although in Missouri it maybe 10 seems that d i o x i n is the e n v i r o n m e n t a l issue, t h e r e are a 11 n u mber of o ther issues b e f o r e the p u b l i c a b o u t e n v i r o n m e n t a l 12 c o n t a m i n a t i o n with other c o m p o u n d s that h a v e the p o t e n t i a l for 13 toxic effect. 14 We do have the luxury with TCDD of having substantial 15 human toxicity information w h i c h we, of course, should use in 16 evaluating potential toxicity of TCDD in various situations. 17 We' r e often left with trying to e x t r a p o l a t e from animal data to 18 man in terms of estimating. 19 In this case, we can modify those data which we've 20 generated in e x p e r i m e n t a l a n i m a l s w i t h d a t a we h a v e in m a n to 21 arrive, I think, at a m o r e i n f o r m e d d e c i s i o n r e l a t i v e to the 22 p o t e n t i a l for d i o x i n to c a u s e a t o x i c e f f e c t in a n y p a r t i c u l a r 23 situation. 24 I think in m y p r e s e n t a t i o n I'd like to s t i c k as close 25 to the s c i e n t i f i c data base as I can. W i t h this issue of T C D D _______________________ 117____________________ _____________ ` BREDEMAN & ASSOCIATES, INC. 0 1 and the gross politicization of it, one hears claims for the 2 absence or exi s t e n c e of a ha z a r d from e x p o s u r e to T C D D that 3 really is not backed by a s c i e n t i f i c d a t a base. T h e r e are 4 excesses on both sides, people claiming risk when the 5 scientific data base does not support the fact that there's 6 risk, others claiming that there's not risk when the scientific 7 data base would suggest m a y b e there is some. So there are 8 excesses on both sides. 9 I think i t 1s important for a group such as this that 10 the d e c i s i o n s b a sed oh the s c i e n t i f i c d a t a b a s e be s e p a r a t e d 11 from those w h i c h are b a s e d l a r g e l y on s p e c u l a t i o n . I t h i n k 12 s p e c u l a t i o n is e s s e n t i a l in this k i n d of an issue, b u t y o u 13 ought to have a clear k n owledge that this is s p e c u l a t i o n and 14 this is science. I think if one m a k e s that d i s t i n c t i o n b e t w e e n 15 speculation and decisions based on science in this issue it 16 would probably be easier to approach this very d i f f i c u l t task 17 that you have before you in trying to d e c i d e w h a t to do with 18 this issue that faces the State of Missouri. 19 So I 'll try to p o i n t out those areas in w h i c h there 20 is a scientific date base to s u p p o r t a p a r t i c u l a r p o i n t of v i e w 21 and those w here it's l a r g e l y s p e c u l a t i o n . So w i t h that sort of 22 preface, let's look at some slides. 23 The first siide y o u ' v e seen a number of times today. 24 So w e ' 11 not dwell on it. H e r e is a l i s t i n g of h u m a n p o i s o n i n g 25' cases with T C D D , and y o u ' v e seen these b e f o r e , p e r h a p s , in a 118 BREDEMAN & ASSOCIATES, INC. i * X slightly different form. Let's spend just a little time on 2 them 3 The dozen or so industrial accidents involving worker 4 exposure, Perhaps in excess of 600 were m a d e ill by these 5 exposures, and that is a data base that is a v a i l a b l e to us. 6 The u n f o r t u n a t e part a b o u t it is in those a c c i d e n t s we d i d n ' t 7 really have a good measure of what the exposure level was, 8 although it's clear that in most of the cases where the 9 exposure took place as a result of an explosion of a reaction 10 ve ssel involved in the s y nthesis of 2,4,5 t r i c h o l o r p h e n o l , XX w h i c h is m o s t of these, that the TCDD r e s i d u e s in t h o s e 12 e x p l o s i o n s p r o b a b l y a p p r o a c h e d 1,000 p a r t s p e r m i l l i o n and 13 sometimes exceeded that so that there was a s u b s t a n t i a l TCDD 14 c o n t a m i n a t i o n e x i s t e n t w i t h i n these f a c t o r i e s as a r e s u l t of 1 15 these accidents. 16 The Seveso, Italy occurrence M a y 10, 1976, it was an X7 event that is a p a r t i c u l a r l y i m portant one in the h i s t o r y of 18 human exposure to TCDD b e c a u s e it was the first i n c i d e n t in 19 which there was substantial exposure of women, p a r t i c u l a r l y 30 pregnant women, and children to TCDD. Prior to that, it had 31 been mostly industrial worker p o p u l a t i o n s p r e d o m i n a n t l y if not 22 e x c l u s i v e l y male. 23 This was an e v e n t w h i c h a l l o w e d us to in this 24 incident look at the p o t e n t i a l for e x p o s u r e to T C D D to c a u s e \ 35 r e p r o d u c t i v e toxic i t y in f e m ales and to c a u s e b i r t h d e f e c t s in ,________________ 119______________________ BREDEMAN & ASSOCIATES, INC. 2 o f f s p r i n g of those fema l e s , and it a l s o let us l o o k at 2 sensitivity of children to dioxin exposure by the dermal root. 3 A n o t h e r i n c i d e n t is c h e m i s t s i n v o l v e d in the 4 synthesis of TCDD, a minor event, and we'll not spend any time 5 and, of course, the Missouri horse show ring incident you know 6 well 1 A number of people have shown this slide before. 8 There's one amplification that I have added there at the last. 9 T h i s is a listing of the acute single dose LD50 of TCDD in a 10 n u m b e r of species, and t h e y ' r e listed there: g u i n e a pig m o s t 11 sensitive, hamster the least sensitive. So that w h e n yo u hear 12 the s t a t e m e n t that T C D D is the m o s t toxic s y n t h e t i c c h e m i c a l w e 13 know, you really have to say what species are you talking about 14 bec a u s e there are a number of compounds more toxic to the 15 hamster than TCDD, a number of compounds more toxic to the 16 bu l l f r o g than TCDD so that you have to ask what spec i es are you 17 referring to when you m a k e that statement. 18 So I think it d o e s n 't d e t r a c t f r o m the f a c t that is 19 an e n o r m o u s l y p o t e n t c o m p o u n d in s o m e spe c i e s , p a r t i c u l a r l y 20 g u i n e a pig, but I think one has to keep it all in p e r s p e c t i v e 21 in look i n g a c r o s s a numb e r of d i f f e r e n t species. 22 You see there at the last that I've g ot w h a t is the 23 acute lethal dose of TCDD in humans and a q u e s t i o n mark, but 24 p a r e n t h e t i c a l l y I've added in e xcess of 100 micrograras per 25 k i l o g r a m . That data is p r o b a b l y the o n l y data t h a t we h a v e of 120 BREDEMAN & ASSOCIATES,.INC 4 1 a d ose r e s p o n s e in h u m a n s , and it came f r o m a s e r i e s of s t u d i e s 2 that were carr i e d out in H o m e s b u r g Pr i s o n in P e n n s y l v a n i a in 3 1964 to 1968 by Dr. Klegman (Phonetic) from the University of 4 P e nnsylvania in which he exposed prisoners der m a l l y to TCDD. 5 The initial purpose of the experiments was to find 6 out wh a t d o s e of TCDD a p p l i e d d e r m a l l y would, in fact, c a u s e 7 chloracne in those prisoners. Initial experiments dealt with 8 c o n c e n t r a t i o n s of .2 m i c r o g r a m s up to 16. m i c r o g r a m s tot a l 9 applied to the skin in acetone. Those doses did not, in fact, 10 produce any chloracne in those prisoners. 11 S u b s e q u e n t e x p e r i m e n t s about w h i c h the d a t a is not as, 12 c o m p l e t e e x t e n d e d the d o s e up to 7,500 m i c r o g r a m s to s o m e 13 individuals again applied dermally to the skin. So that those 14 i n d i v i d u a l s got 7,500 m i c r o g r a m s applied over a t w o - w e e k period 15 to the skin disso l v e d in acetone. 16 C o n t r a r y to what might have been stated today, TCDD 17 a p p l i e d to the skin of a n i m a l s in a c e t o n e is a l m o s t 100 p e r c e n t 18 a b s orbed. So that the dose in some of those i n d i v i d u a l s was in 19 e x c e s s of 100 m i c r o g r a m s per k i l o g r a m and c h l o r a c n e w a s 20 p r o d u c e d in those individuals, but Dr. K l e g m a n 1s s t a t e m e n t was 21 that there was no other evidence, no other c l i n i c a l s y m p t o m s of 22 tox i c i t y . 23 The s u b j e c t r e m a i n e d well t h r o u g h o u t the s t u d y so \ 24 that we have a c ase in w h i c h we've e x p o s e d h u m a n s to a d o s e of 25 a b o u t 100 m i c r o g r a m s per k i l o g r a m sort of in the d o s e t h a t ' s 121 B R E D E M A N , A S S O C I A T E S , INC.  1 lifted there for rabbit and dog but no clinical symptoms of 2 tp?cieity other than the chloracne. 2 These, of course, the other species there where the '4 d p s e w a s a p p l i e d orally, in this case it w a s a p p l i e d d e r m a l l y , $ b u t 9.ne C 9m m o n p o i n t of r e f e r e n c e is T C D D a p p l i e d to the r a b b i t $ kin is a b o u t half as toxic if it is a d m i n i s t e r e d orally. So 7 ypu can sprt of d o u b l e those numb e r s if you w a n t e d to e s t i m a t e 9 Whot the tpxicity might be applied as a pure compound dermally. 9 So that we do have some human data suggesting that humans may IQ bp one of the species less susceptible to the acute lethal II effects 9f TPP 9?/ perhaps, even to the sub-acute toxic 12 effects pf TCPP 13 This, pf course, does not say anything about human 14 susceptibility to the chronic effects of TCDD, although we do 15 ha v e e p i d e m i o l o g i c a l studies w h i c h w e 'll talk abo u t in just a U few minutes* 17 Jipoking at r e p r o d u c t i v e tox i c i t y , I 've l i s t e d here 19 fbsf dose whiph is sprt of the min i m u m dose which causes 19 reproductive toxicity across a number of species. Listed there t 29 fpr the monkeys I have not listed the data that was generated 21 b y A l l a n at W i s c o n s i n . T h a t data is s u b j e c t to c o n s i d e r a b l e 22 c o n t r o v e r s y in terms of the c o n d u c t of those s t u d i e s and the 23 validity pf them. % think the data can't be completely ignored 24 but i think should be accepted with considerable skepticism 25 until they __________________ are repeated by some laboratory. 122____________________ ______________________________________________________________________________________________________ BREDEUAN & ASSOCIATES, INC.  1 But you can see that r e p r o d u c t i v e t o x i c i t y is seen in 2 m o n k e y s in another s t u d y at .05 m i c r o g r a m s per k i l o g r a m per 3 day, a fairly sensitive species. 4 Reproductive toxicity also seen in rats at .01. No 5 effect level is .001. W h a t ' s i n t e r e s t i n g h e r e is t h a t in that 6 third line we see mice males exposed to 2.4 m i c r o g r a m s per 7 kilogram per day during about a 70-day period looking for 8 a b i l i t y to p r o d u c e r e p r o d u c t i v e t o x i c i t y in m a l e m i c e and it 9 was w i t h o u t effect. T h a t is a f a i r l y s u b s t a n t i a l dose. If 10 y o u ' d incr e a s e that d o s e v e r y m u c h over the p e r i o d in w h i c h 11 this was a d m i n i s t e r e d , we w o u l d l ike to h a v e b e g u n to h a v e some 12 f a i r l y s e vere toxic e f f e c t s . 13 This is a s o - c a l l e d d o m i n a n t l e t h a l e f f e c t , and it 14 measures the ability of a compound to cause reproductive 15 toxicity in males, and you can see that, in fact, it had no 16 e f f e c t . 17 The data currently available suggests that TCDD does 18 have reproductive toxicity, but it m a y be that it o n l y has 19 reproductive toxicity in the female of species and not the male. 20 This data suggests that. It c e r t a i n l y d o e s n ' t c o m p l e t e l y 21 s u p p o r t that p o i n t of view, b u t it is a h y p o t h e s i s t h a t 22 c e r t a i n l y needs further i n v e s t i g a t i o n 23 As far as humans are concerned, there was no evidence 24 of reproductive toxicity in the S e v e s o a c c i d e n t . The New 25 Zealand study which Dr. Murray showed you this morning where _______________________ 123 ______________________________ BREDEMAN & ASSOCIATES, INC.  1 they looked at r e p r o d u c t i v e t o x i c i t y in w o r k e r s e x p o s e d to. T C D D 2 by virtue of being exposed to the phenoxy herbicides doesn't 3 indicate evidence of a toxic effect either. 4 There was a study out of Dow looking at reproductive 5 t o x i c i t y in w o r k e r s e x p o s e d to p h e n o x y h e r b i c i d e m a n u f a c t u r e . 6 A g a i n , no evidence of reproductive toxicity in those c o u p l e s 7 So that it is u n c lea r at this time w h e t h e r the levels, of 8 exposure to TCDD that have occurred in humans has any effect on 9 reproductive toxicity. 10 Tera t o l o g y , it is a f a i r l y g o o d c o m p o u n d at p r o d u c i n g 11 b i r t h d e f ects in m i c e with a level of 1 to 3 m i c r o g r a m s p e r 12 k i l o g r a m per d a y during the s e v e n t h to the f i f t e e n t h d a y of 13 gestation, the critical period for b i r t h ' d e f e c ts in that 14 species, whereas in rats even hi g h e r d o s e s d o n ' t c a u s e b i r t h 15 d e f e c t s but it does c a u s e t o x i c i t y in the f e t u s e s m a n i f e s t e d in 16 h y d r o n e p h r o s i s , a d e f e c t in the kidn e y , not a real b i r t h d e f e c t , 17 b u t m o r e a toxic e f f e c t on rats. 18 In the monkeys, although one saw increased incidence 19 of s p o n t a n e o u s a b o r t i o n at these levels, we d i d no t see 20 e v i d e n c e of any b irth d e f e c t s in t h o s e a b o r t e d f e t u s e s . In the 21 Seve s o incident, the only i n c i d e n t in w h i c h we h a v e had 22 substantial exposure to p r e g n a n t w o m e n to T C D D , we did not see 23 evide n c e of teratolo d y in t h o s e 24 DR. POWELL: Are you saying there were no higher 25 incidences of birth d e f e c t s in S e v e s o ? _________ 124_________________________ _____________ ' BREDEMAN & ASSOCIATES, INC. 9 1 DR. NEAL: T h e r e ' s not a s i g n i f i c a n t i n c r e a s e in 2 birth defects in the Seveso incident. 3 DR. POWELL: As of w h e n ? I m e a n , is this something 4 brand new? 5 DR. NEAL: This is starting-- 6 DR. POWELL: Talking about with the 1978 incident. 7 Is this a conclusion that's been recently reached? 8 DR. NEAL:- I think it's been c o n s i s t e n t t h r o u g h o u t 9 all of the teratology studies that have been done in Seveso. 10 Looking at the incidence of cancer in experimental 11 a n i m a l s , h e r e is a list i n g . I t h i n k y o u ' v e s e e n t h e s e b e f o r e . 12 I think the one a d d i t i o n to the d a t a that w a s p r e s e n t e d t o d a y 13 is that in the b o t t o m line y o u see the e x p o s u r e of S w i s s m i c e 14 d e r m a l l y to TCDD .0 05 m i c r o g r a m s t h r e e t i m e s a w e e k fo r 99 15 weeks does produce an increased incidence of f i b r o s a r c o m a s in 16 m ice. This is a p a r t i c u l a r l y i m p o r t a n t f i n d i n g , I think, 17 vis-a - v i s the suggestion that soft tissue tumors m a y be 18 associated with phenoxy herbicide exposure in work e r 19 populations. 20 I t hink this is an i m p o r t a n t f i n d i n g that lead some 21 a d d i t i o n a l cred e n c e to the fact that this i ssue of s o f t t i s s u e 22 s a r c o m a s in expo s e d h uman p o p u l a t i o n s need to be e v a l u a t e d in 23 greater d e t a i l . 24 These are some of the epidemiological studies that 25 have been done. Of course, the Swedish studies with the forest 125 B R E D E M A N , A S S O C I A T E S , INC. $: 1 workers are actually two studies with Hardell being the major 2 author. They did see an increase of soft tissue sarcomas. 3 T h e y also in the second study some evidence of an increased 4 incidence of m a l i g n a n t l y m phoma in these p o p u l a t i o n s , b o t h 5 H o d g k i n 1s d i s e a s e and n o n - H o d g k i n 1s l y m p h o m a . 6 A similar study in F i n l a n d w h i c h looked at a similar 7 p o p u l a t i o n as was e x a m i n e d in the S w e d i s h s t u d y h a v e n o t s een 8 this increased incidence of soft tissue sarcomas or lymphoma, 9 a l t h o u g h the p e r i o d from e x p o s u r e to e x a m i n a t i o n w a s l ess in 10 the F i n n i s h s t u d y than in the S w e d i s h study. 11 A l s o , a r e c e n t s t u d y in N e w Z e a l a n d in w h i c h a g a i n 12 w o r k e r s e x p o s e d to p h e n o x y h e r b i c i d e s in its a g r i c u l t u r a l use 13 did not s h o w a r e l a t i o n s h i p b e t w e e n that -o c c u p a t i o n a l e x p o s u r e 14 and soft tissue sarcomas. 15 Nevertheless, the result of the Swedish study and the 16 f act that in two st u d i e s d o n e in the U n i t e d S t a t e s t h e r e is 17 evidence of soft tissue sarcomas which exceed that which was 18 e x p e c t e d , i n d i v i d u a l l y e a c h of these s t u d i e s is n o t a 19 significant finding. But when you combine those three findings 20 t o g e t h e r , it is s u g g e s t i v e that there m a y be a r e l a t i o n s h i p and 21 certainly needs to be explored. 22 I think the key thing is that in the S w e d i s h s t u d i e s 23 these individuals were exposed to a large number of diffe r e n t 24 c o m p o u n d s : the phe n o x y h e r b i c i d e s , the c h i o r o p h e n o l s , and 25 o t h e r h e r b i c i d e s in a d d i t i o n to 2 , 4 , 5-T w h e r e t h e y m i g h t h a v e 126 BREDEMAN & ASSOCIATES, INC. 1 been exposed to the TCDD. 2 In addition, there seemed to be a relationship 3 between soft tissue sarcomas and exposure to herbicides not 4 containing the 2,3,7,8 isomer. So that I think on balance one 5 cannot see a cause effect relationship between soft tissue 6 sarcomas and exposure to the TCDD itself, but the relationship 7 is s u f f i c i e n t that I think it c e r t a i n l y r e q uires some 8 additional emphasis on the part of epidemiological studies 9 looking to either r e i n f o r c e that r e l a t i o n s h i p or indicate t h a t , 10 p e r h a p s , t here is not a r e l a t i o n s h i p . 11 In the s t u d y in G e r m a n y , there was an i n c r e a s e d 12 i n c i d e n c e of g a s t r o i n t e s t i n a l tumors, a l t h o u g h the n u m b e r of 13 individuals examined was about 50 and the statistical 14 significance of this is also open to some question I think 15 p a r t i c u l a r l y s ince i t 's not s e e n in other e p i d e m i o l o g i c a l 16 s t u d i e s of i n d i v i d u a l s w h o w e r e , in fact, e x p o s e d to T C D D and 17 developed c h l o r a c n e . 18 I think another issue relative to soft tissue 19 s a r c o m a s is that in E u r o p e a n p o p u l a t i o n s of i n d u s t r i a l w o r k e r s 20 who developed chloracne as a result of exposure to TCDD there 21 d i d n ' t seem to be any r e l a t i o n s h i p b e t w e e n that e x p o s u r e and 22 soft tissue sarcomas as well. 23 The final s t udy, the Nitro, W e s t V i r g i n i a study, has 24 b e e n d i s c u s s e d b e f o r e . No s i g n i f i c a n t i n c r e a s e in c a n c e r 25 m o r t a l i t y . No s i g n i f i c a n t i n c r e a s e in m o r t a l i t y overall, but 127 BREDEMAN & ASSOCIATES, INC. ft 1 again, it was 121 i n d i v i d u a l s , a f a i r l y small p o p u l a t i o n . 2 One cannot draw definitive conclusions from that, 3 although I think you need to realize that from a study like 4 that you certainly get a perception of what the level of risk 5 below what the upper level of risk m i g h t be and so that these 6 kinds of studies although small do give you valuable 7 information and you have to realize that these people were 8 l i k e l y e x p o s e d to f a i r l y h e a v y d oses. So t h a t I t h i n k one c a n -- tt 9 this information is v a l u a b l e in m a k i n g some overall assessment 10 of what risk m i g h t be to individuals exposed to low levels of 11 TCDD. 12 Here are some listing of other toxic effects in 13 e x p e r i m e n t a l a n i m a l s that we will not spend any time on e x c e p t 14 that final one w h e r e T C D D d o e s c a u s e i n d u c t i o n .of a l a r g e 15 n u mber of e n z y m e s p a r t i c u l a r l y in the r o d e n t live r s . To d a t e 16 activities of a dozen enzymes are induced, but there seems to 17 be no c l i n i c a l s i g n i f i c a n c e b e t w e e n that i n d u c t i o n and the 18 toxic effects seem to be no connection between the induction 19 e n z y m e s and any of the t o x i c e f f e c t s that are seen. In other 20 w o rds, s t a t e d m o r e c l e a r l y , e n z y m e i n d u c t i o n i t s e l f d o e s not 21 c a u s e any t o xicity. 22 Other toxic e f f e c t s seen in TCDD e x p o s e d humans are 23 listed here and other p e o p l e h a v e t a l k e d a b o u t them. One 24 e f f e c t that m a y not h a v e b e e n d i s c u s s e d in m u c h d e t a i l was the 25 h y p e r c h o l e s t e r o l e m i a and h y p e r l i p i d e m i a that has been seen 128 BREDEMAN & ASSOCIATES, INC  1 reasonably c o n s i s t e n t l y in h e a v i l y exposed human populations. 2 The clinical i m p l i c a t i o n of this is unclear, b u t n e v e r t h e l e s s 3 it is seen as a fair l y consistent effect of TCDD exposure where 4 the exposure has been fairly heavy. 5 You notice I have not included porphyria cutanea 6 tarda b e c a u s e I think t h e r e 's r e a s o n a b l e d a t a to s u g g e s t that 7 it m a y not b.e r e l a t e d to T C D D e x p o s u r e . It has o c c u r r e d in a 8 couple of cases, but its i n c o n s i s t e n t a p p e a r a n c e of it in h u m a n 9 populations even those that they are heavily to TCDD suggests 10 that in those few cases the porphyria may have resulted from 11 exposure to other compounds to which the workers were exposed 12 d u r i n g that incident. 13 Some Canadian scientists have made a .fairly detailed 14 r e v i e w of the data of h u m a n a n d a n i m a l t o x i c i t y of T C D D in 15 documents that have been published recently also come to that 16 same conclusion that they q u e s t i o n whether there's a 17 r e l a t i o n s h i p b e t w e e n T C D D a n d p o r p h y r i a c u t a n e a t a r d a in man. 18 H ere is a g a i n s h o w i n g of t h a t P o i g e r (Phonetic) and 19 Slater (Phonetic) data on dermal absorption of TCDD depending 20 u p o n the v e h i c l e in w h i c h i t 's found. 21 One c o r r e c t i o n is that the m e a s u r e m e n t that they 22 p e r f o r m e d is r e a l l y the p e r c e n t of the d o s e in the liver after 23 t w e n t y - f o u r h o u r s rather than the p e r c e n t a b s o r b e d as was 24 indicated earlier today. 25 I t h i n k one i m p o r t a n t p o i n t in trying to c o r r e l a t e 129 BREDEMAN & ASSOCIATES, INC. f this data with dermal e x p o s u r e in the M i s s o u r i s i t u a t i o n is 2 that the soil, the exposure to soil in this case was as a soil 3 water paste which would maximize dermal contact between the 4 soil and the skin, and in a n o r m a l s i t u a t i o n e x p o s u r e to the 5 dirt would be in its g r a n u l a r fo r m so that the s u r f a c e c o n t a c t 6 would be only a fraction of that wh i c h is d e p i c t e d here. It 7 says that the percent absorbed would undoubtedly be much less 8 than even depicted here. 9 So that the effect of soil on absorption of.TCDD 10 through the skin is, it's c o n s i d e r a b l y a t t e n u a t e d b y it b e i n g 11 o b s e r v e d onto soil. 12 I'm going to g e t t h r o u g h r a t h e r e a r l y h e r e b e c a u s e 13 we're s k i p p i n g over a lot of d a t a t h a t ' s h e e n r e p e a t e d . L e t m e 14 just then summarize. 15 Acute toxicity of TCDD vari e s w i d e l y in animals. The 16 e v i d e n c e c u r r e n t l y a v a i l a b l e s u g g e s t s m a n m a y be one of the 17 less s e n s i t i v e species to the a c u t e and, p e r h a p s , s u b a c u t e 18 toxic effects of TCDD. 19 This does not say one cannot generalize from that 20 that they may also be less sensitive to the chronic t o x icity 21 e f f ects of TCDD a l t h o u g h one l ooks at the e p i d e m i o l o g i c a l 22 studies that have been done in w o r k e r s who were e x p o s e d to T C D D 23 to the p o int that they d e v e l o p e d c h l o r a c n e a n d o t h e r c l i n i c a l 24 symptoms and it would s u g g e s t that m a n m a y a l s o be r e a s o n a b l y 25 resistant to the c h r o n i c e f f e c t s of T C D D p a r t i c u l a r l y in tho s e 130 BREDEMAN & ASSOCIATES, INC.  .1 s t u d i e s w h e r e the time b e t w e e n e x p o s u r e and e x a m i n a t i o n has 2 been twenty to thirty years. 3 Common symptoms in humans are chl o r a c n e , and m y 4 i n t e r p r e t a t i o n of the data is that if the r o o t of e x p o s u r e is 5 dermal y o u 1re not going to have any other symptoms of t o x icity 6 of TCDD in the abse n c e of chloracne. T h a t ' s a m a t t e r of 7 interpreting that data; but as you look at the industrial 8 a c c i d e n t s that hav e occurred in the Seveso i n c i d e n t and look at 9 the percentage of people complaining about a particular toxic 10 e f f e c t of that e x p o s u r e , w i t h o u t e x c e p t i o n c h l o r a c n e e x c e e d s 11 the other symptoms by a substantial p e r c e n t a g e so that m y 12 feel i n g is that if the root of e x p o s u r e is d e r m a l as it is in 13 almost all of these cases the first symptom that is going to be 14 seen is chloracne and then in the abse n c e of c h l o r a c n e 15 i n d i v i d u a l s are not likely to be s u f f e r i n g f r o m a n y o t h e r 16 symptom of TCDD toxicity. Other symptoms of TCDD toxicity are 17 s h o w n here. 18 TCDD do e s prod u c e cancer in m i c e a nd rats. No cau s e 19 effect r e l a tionship between T C D D e xposure and c a n c e r has yet 20 been shown in man; but b e c a u s e of that s u g g e s t i o n of a 21 r e l a t i o n s h i p b e t w e e n e x p o s u r e and soft t i s s u e t u m o r s , it 22 certainly needs to be investigated further. 23 As a number of i n d i v i d u a l s h a v e i n d i c a t e d t o d a y , the 24 availability of TCDD for dermal absorption r e a l l y varies with 25 the formulation. If it's in an e a s i l y e v a p o r a b l e s o l v e n t s uch 131 BREDEMAN & ASSOCIATES, INC 9 1 as acetone or methanol, the skin a b s o r p t i o n is s u b s t a n t i a l , 2 p e r h a p s as m u c h as 100 p e r c e n t of it. If it's in soil, the 3 absorption is considerably attenuated. Thank you. 4 CHAIRMAN JUDGE FINCH: Do some of the Task Force have 5 questions of D r . Neal? 6 DR. ROUSH: What about half life? 7 DR. NEAL: Yes. The question was what about half 8 life. What is the half of T C D D in a nimal o r g a n i s m s . T h e r e ' s a 9 s u b s t a n t i a l data b a s e on that. Th e s p e c i e s in w h i c h t h e r e is 10 the s h o r t e s t half life is the h a m s t e r w h e r e the h a l f l ife is 11 a b o u t e l e v e n to f i f t e e n days, in other w o r d s , h a l f of a dose. 12 If you g i v e a h a m s t e r a dose of TCDD, h alf of - t hat d o s e has 13 b e e n e x c r e t e d in two w e e k s . T h e n the h a l f t h a t is r e m a i n i n g , 14 h a l f of that is e x c r e t e d in a n o t h e r two w eeks. So that it 15 halves it every two weeks. 16 As y o u l o o k at the g u i n e a pig and the rat, the h a l f 17 life is a bout thirty days so that h a l f of a d o s e t h a t yo u h ave 18 g i v e n to a rat or a g u i n e a pig is g o n e and e x c r e t e d in t h i r t y 19 d a y s and in t h irty m o r e d a y s h a l f of w h a t ' s r e m a i n i n g is 20 e xcreted and it continues. 21 The cow has a h a l f life of a b o u t 120 days. The 22 m o n k e y a half life of about 70 days. The goa t s o m e t h i n g like 23 100 days. 24 DR. ROUSH: And man? 25 DR. NEAL: So that one has to say w h e r e does m a n fit 132 BREDEMAN & ASSOCIATES, INC 1 into this, I think if you look at it in terms of man's' size 2 relative to other animals there seems to be as you get larger 3 there is a longer half life, I would suggest, p e r haps, m a n 4 does fit at the 100 day half life area. 5 I think the thing that supports perhaps that man does * 6 h a v e a f a i r l y r e a s o n a b l e h a l f l ife 'is t hat t h e r e h a v e b e e n a *i *! 7 n u m b e r of o c c a s i o n s w h e r e t h e r e h a v e b e e n a t t e m p t sIIi to m e a s u r e 8 TCDD levels in human tissues subsequent to an exposure to T C D D , 9 and all except one of these measu r e m e n t s have not revealed the 10 p r e s e n c e of TCDD in adip o s e tissue or plasma. 11 T his one e x c e p t i o n is a w o m a n in S e v e s o jwho d i e d some 12 s e v e n m o n t h s after the a b s e n c e of a p r i m a r y liver tumor. The 13 t umor e x i s t e d b e f o r e the e x p o s u r e , b u t they d e t e c t e d T C D D in 14 the liver of that woman and that was an unequivocal analytical 15 f i n d i n g 16 But there have been a number of other attempts in I\ 17 h u m a n s and w i t h o u t s u c c e s s in d e t e c t i n g the T C D D iiin the h u m a n 18 m a l e plasma and tissues so that it would suggest that it has a 19 reasonable half life and is excreted and probably falls into 20 that r ange of 15 to 120 days that exists for other animal 21 s p e c i e s that have b e e n e x a m i n e d . 22 DR. POWELL: I was wondering if you also feel as 23 s o me o n e else m e n t i o n e d this morn i n g that if you ingest d i o x i n 24 som e h o w this will a l s o -appear first, any symptoms will appear 25 first before chloracne? 133 BREDEMAN & ASSOCIATES, INC. 1 DR. NEAL: Yes The only human exposure situation 2 that we have where we can answer that with some reasonable 3 certainty is the Yusho incident in Japan. Now, this was not 4 TCDD. This is 2,3,7,8 t e t r a c h l o r o d i b e n z o f u r a n , but the 5 experimental data suggests that there is, I think, 6 unquestionably the mechanism by which the dibenzofuran, 7 t e t r a c h l o r o d i b e n z o f u r a n c a u s e s its t o x i c i t y is id e n t i c a l to the 8 mechanism by which TCDD causes its toxicity. And the toxicity 9 of the dibe n z o f u r a n is not g r e a t l y d ifferent in the guinea pig. 10 D i b e n z o f u r a n s LD50 is 5 m i c r o g r a m s , an e x t r a o r d i n a r i l y low or 11 e x t r a o r d i n a r i l y h i g h l evel of t o x i c i t y in e x t r a o r d i n a r i l y low 12 d o s e to c a u s e t o x i c i t y . -* 13 In that Y u s h o i ncident, we did,' in fact, have 14 substantial ingestion of the d i b e n z o f u r a n, and you look at the 15 complaints of s y m p t o m s in the Yus h o p a t i e n t s . The symptom that 16 p r e d o m i n a t e d was, in fact/ c h l o r a c n e . 17 My f e e ling is that, and I'll go b a c k to a n i m a l data 18 now, in the r a b b i t y o u can p r o d u c e c h l o r a c n e by g i v i n g the 19 animal TCDD i n t e r p e r i t o n e a l y but the level r e q uired is higher 20 than if you apply it d e r m a l l y to the ear itself. 21 But I still th i n k that the p r e d o m i n a n t s y m p t o m s are 22 going to be chloracne, but I'll r e s e r v e the fact that there may, 23 in fact, be o ther s y m p t o m s of t o x i c i t y by oral i n g e s t i o n . But 24 in a p o p u l a t i o n g r ou p , the p r e d o m i n a n t s y m p t o m s that are going 25 to be seen is c h l o r a c n e I'll us e t h a t Yusho inci d e n t and the 134 BREDEMAN & ASSOCIATES, INC 1 incident in T a iwan w h i c h is j u s t a r e p e a t of the Y u s h o in a 2 subst a n t i a l p o p u l a t i o n 2 , 0 0 0 in T a i w a n , s o m e t h i n g like 1,200 in 3 in the Yusho. So we have a f a i r l y s u b s t a n t i a l human population 4 exposed orally to a compound which exerts as toxicity the same 5 way that TC D D ch l o r a c n e is the m a j o r symptom. 6 DR. POWELL: Let me go back for a minute to this 7 question of problems with birth defects at Seveso. I'm looking 8 at some studies here that indicate-- and they aren't saying this 9 is a conclusive study. This is 1980 or 1981, I guess. There 10 are incre a s e d i n c i d e n c e s of b i r t h d e f e c t s , D o w n ' s S y n d r o m e is 11 one that t h e y -- I m e a n , they a r e n ' t s t a n d i n g up and b e a t i n g a 12 drum. T h e y a r e n ' t s a ying it's a b s o l u t e l y the case. T h e y ' r e 13 more saying "Well, we've got s o m e t h i n g in one case. The factor 14 is a factor of 100 in cases o f -- and they say that it's just 15 something that has to be followed and they have to do further 16 base line s tudies. 17 Now, that's why I asked y o u was this a c o n c lusion 18 that's r e c e n t l y been r e a c h e d that you w e r e s a y i n g ? 19 DR. NEAL: No. At the beginning of m y talk, I said 20 I'm going to only cite those b i o l o g i c a l effects for which 21 t h e re's a s c i e n t i f i c d a t a b a s e to s u p p o r t it. T h a t i n c i d e n c e 22 of birth d e f e c t s in the S e v e s o area, the e x p o s e d area v e r s u s 23 the control area in the L o m b a r d i , t h e r e wa s not a s t a t i s t i c a l l y 24 significant i n c r e a s e 25 It is p a r t i a l l y a f u n c t i o n of the small numbers that 135 BREDEMAN & ASSOCIATES, INC. 1 were generated during that time, but the s c i e n t i f i c -- if you 2 look at this data sc i e n t i f i c a ll y , there is not a s t a tistical 3 significant increase in b i r t h d e f e c t s in that p o p u l a t i o n . 4 DR. POWELLS But we need a larger population. 5 DR. NEAL: But I think s u p p o r t i n g that also is the 6 other studies that have been done of r e p r o d u c t i v e toxicity in 7 other populations. 8 The New Zealand study which is a fairly substantial 9 one would tend to support that point of vie w as well. 10 MR. F O R R E S T E R : Has t here b e e n a n y r e p r o d u c t i v e 11 s t u d i e s around the Y usho d i b e n z o f u r a n i n c i d e n t s ? 12 DR. NEAL: The o n l y r e p r o d u c t i v e -- t h e r e w e r e s o m e 13 increased incidents of spontaneous a b o r t i o n in those p eople in 14 the Y u s h o incident. The d a t a , I think, in the T a i w a n i n c i d e n t 15 hasn't b e e n -- so that there was a s i g n i f i c a n t i ncrease in 16 incidence of spontaneous a b o r t i o n in the Yusho incident, 17 s i g n i f i c a n t incre a s e in low for g e s t a t i o n a l w e i g h t b a b i e s . 18 In other words, the w e i g h t of the b a b y at b i r t h was 19 less than it should be, b u t these were s u b s t a n t i a l e x p o sures. 20 These people were quite ill. The babies had skin changes at 21 birth. 22 DR. M A R I E N F E L D : H o w long ago did K l e g m a n do his work? % 23 DR. NEAL: 1964 to '67. 24 DR. MARIENFELD: Have those i n d i v i d u a l s b e e n followed? 25 DR. NEAL: I think they* re lost. T h e y c e r t a i n l y ______________________________ 136_______________________________________________ BREDEMAN & ASSOCIATES, INC. would be a great population to follow because here we have 2 r e a l l y our on l y good data of dose r e s p o n s e in huma n s , and it is 3 u n f ortunate that the initial p o p u l a t i o n in the lower dose 4 studies was about 60 5 The population in the higher dose studies was 10. So 6 that the ones which got the substantial doses of 7,500 7 m i c r o g r a m s were m u c h smaller in number. 8 DR. MARIENFELD: Has any attempt been made to locate 9 them? 10 DR. NEAL: I d o n ' t h a v e f i r s t - h a n d k n o w l e d g e of that. 11 I w ould think there p r o b a b l y has not been. I think the legal 12 r a m i f i c a t i o n s of a f o l l o w up of that p o p u l a t i o n p a r t i c u l a r l y f 13 since the climate for use of prisoners in these kinds of study 14 has radically changed since that was a common practice would 15 suggest that p r obabl y no one is eager to p u r s u e that. 16 C H A I R M A N JUDGE FINCH: Or even will i n g . 17 MR. DOUGLA S : W e ' v e t alked a b o u t h a l f life and that 18 subject. We often hear that it's bioaccumulative. W h a t about 19 that? 20 DR. NEAL: No. It is e x c reted in b o t h u r i n e and 21 feces, and it is the m e t a b o l i t e s that's e x c r e t e d . T h a t ' s b e e n 22 a m a j o r rea of r e s e a r c h in m y l a b o r a t o r y is e x a m i n a t i o n of the 23 m e t a b o l i s m of this com p o u n d . It is m e t a b o l i z e d at a r e a s o n a b l e 24 r a t e . 25 In other words, in the g u i n e a pig if y o u g i v e a d o s e 137 BREDEMAN & ASSOCIATES, INC. B 1 fifteen days later, half that dose is gone if it's all been 2 m e t a b o l i z e d And all animal species we've looked at so far do 3 m e t a b o l i z e it to p r o d u c t s that are m u c h less toxic than the 4 parent compound# So that some compounds that are metabolized 5 are m e t a b o l i z e d to m o r e toxic products, b ut in the case of TC D D 6 as far as the acute toxicity is m e a s u r e d -- 7 MR. DOUGLAS: Where do these statements come from as 8 far as bioaccumulation of it? 9 DR. NEAL: Th e y have no basis in e x p e r i m e n t a l fact 10 b e c a u s e it is a c o m p o u n d w i t h a r e l a t i v e l y s h o r t h a l f life if 11 y o u look at it r e l a t i v e to s ome of the c h l o r i n a t e d -- i 12 p o l y c h l o r i n a t e d b i p h e n o l s w h i c h h a v e a v e r y long h a l f l i f e or 13 aldrin or dieldrin or DDE, the m e t a b o l i t e DDT which have a very 14 long half life. TCDD does not have that. It's not 15 particularly bioaccumulative. 16 MR. DOUGLAS: That's a p a rticular s i g n i f i c a n t 17 o b s e r v a t i o n to me, p a r t i c u l a r l y w h e n you h a v e a p o p u l a t i o n 18 e xpo s e d to normal lev e l s whether or not it is b i o a c c u m u l a t i v e . 19 W h a t y o u ' r e saying is that y o u b r e a k it down. 20 DR. NEAL: Oh, yeah. 21 DR. STALL I N G S : I'd like to offer a c o m m e n t in 22 relationship to the aquatic furans. The relative incidence of 23 the d i b e n z o f u r a n s is about o n e - f o r t y t housandth or o n e - o n e 24 h u n d r e d thou s a n d th that of TCDD in the env i r o n m e n t . I t h i n k 25 the point m i g h t be well c l a r i f i e d if you feed an a n i m a l that is 138 BREDEMAN & ASSOCIATES, INC. 1 no longer exposed to this material, you will see a decline. If 2 the organism is continually exposed to environmental input, the 3 level will be maintained at a level greater than that that is 4 e x po s e d in a q u a t i c organisms. 5 So you m i g h t expand brie f l y on the d i f f e r e n c e in 6 terms of the environmental accumulation versus one dose 7 response. 8 DR. YOUNG: I'll address that for you, show you what 9 studies that we a c t u a l l y have in the e n v i r o n m e n t . 10 C H A I R M A N J U D G E FINCH: Okay, fine. A n y other 11 q u e s t i o n s of the Task F o r c e ? 12 DR. ROUSH: W h a t a b o u t the i m p l i c a t i o n of it b e i n g 13, not m u t a g e n i c ? ' 14 DR. NEAL: Yes. Well, it is a mixed bag of data. 15 Most of the in vitro m e t h o d s for d e tecting a b i l i t y of TCDD 16 c a u s e p e r m a n e n t a l t e r a t i o n of the DN A a r e n e g a t i v e , a l t h o u g h 17 t h e r e ' s a r e c e n t s t u d y out of the Air F o r c e at W r i g h t P a t t e r s o n 18 (Phonetic) that suggests that in a test of m u t a g e n i c i t y not 19 o f ten used there is some s u g g e s t i o n that it is, b u t 20 m e a s u r e m e n t s of c o nvalent binding of TCDD to DNA in a n i m a l s are 21 e s s e n t i a l l y n e g a t i v e . So that I think on b a l a n c e the 22 s u g g e s t i o n is t h a t it p r o b a b l y is not m u t a g e n i c in m o s t s y s t e m s 23 and m a y not be m u t a g e n i c in a nimal s y s t e m s as well. 24 DR. ROUSH: What implications does that have? 25 DR. NEAL: It w o u l d suggest, in fact, that T C D D m a y 139 BREDEMAN & ASSOCIATES, INC I be c a u s i n g an i n c r e a s e in t u mors in e x p e r i m e n t a l a n i m a l s by a 2 promotional rather than by a mechanism causing irreversible 3 change in the DNA, in other words, an initiating me c h a n i s m . 4 I m p l i c a t i o n s of that in terms of risk assessment, 5 though, I think are not-- there's really not much of a way of 6 differentiating between a tumor caused by a promoter and a 7 tumor c a u s e d by i n i t i a t o r is s t i l l a tumor. A n d i f it's a 8 mal i g n a n t tumor, it's going to kill you. 9 I think the o n l y f a c t o r that w o u l d a m e l i o r a t e it is 10 that p r o m o t e r s h a v e to be, y o u h a v e to be e x p o s e d to a p r o m o t e r 11 for a s u b s t a n t i a l p e r i o d of time. A single d o s e d o e s not 12 p r o m o t e . It t akes a s u b s t a n t i a l p e r i o d of p r o m o t i o n b e f o r e a 13 tumor then is s e l f - s u s t a i n i n g . If you stop short of that, then j ! 14 you have to start over at the beginning again. 15 I think a good c o n t r a s t h e r e is a f l a t o x i n . A f l a t o x i n 16 is p r e s e n t in some of our f o ods at a level of 15 p a r t s per 17 billi o n , and it's a l l o w e d in p e a n u t s and c o r n at that level for 18 human consumption. It is a m u c h more potent c a r c inogen than iI 19 TCDD. A single e xposure to one m i c r o g r a m of aflat o x i n will 20 cause h e p a t o m a s in a trout. It is an e x t r e m e l y p o t e n t 21 c a r c i n o g e n . It is an initiator. 22 A single e x p o s u r e will cause tumors. So that it is a 23 m u c h m o r e p o t e n t c a r c i n o g e n than is TCDD, but it's an ji 24 unavoidable c o n t a m i n a n t of our peanuts and our corn because the 25 mold grows on those pro d u c t s and it's just impossible to m a r k e t 140 BREDEMAN & ASSOCIATES, INC. " 7 corn or peanuts without the aflatoxin being present. As far as 2 a c a r c i n o g e n i c risk, the a f l a t o x i n l i k e l y pose's a m u c h m o r e 3 s u b s t a n t i a l risk, than does T C D D b u t an u n a v o i d a b l e one b e c a u s e 4 it is contaminating a food stuff which is part of our diet and 5 that w hich we c a n 't avoid. 6 I think that needs to be kept in p e r s p e c t i v e that s 7 TCDD likely doesn't cause tumors except over an extended period 8 of exposure because the data suggests is a promoter. Aflatoxin, 9 on the other hand, a single exposure to a reasonable dose may, 10 in fact, initiate that p r o c e s s t hat w i l l e v e n t u a l l y e x p r e s s i 11 itself as a tumor. 12 CHAIRMAN ,,JUDGE FINCH: An y other q u e s t i o n s ? Thank I v, . " 13 you very m uch, Doctor. H e a p p r e c i a t e your co m i n g out. *|i 1 i 14 Dr. Donnell. 15 16 17 18 19 20 21 22 23 24 25 BREDEMAN & ASSOCIATES, INC