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Senator HART. Do you know any experiments that point in the direction that it is probably not cumulative?

Dr. VERRETT. I am not aware of any, no. The human data I cited with respect to occupational exposure would also indicate that it is probably cumulative in the human, of course.

Senator HART. You used a word here which I take it means burning.

Dr. VERRETT. Pyrolysis. Not exactly burning. In the sense I used it, it means reacting under conditions of elevated temperature, but not the actual burning of the material itself. It indicates a high temperature reaction, perhaps, heat applied to the material in order to make the reaction take place, but not in the sense of actually igniting it.

But it does indicate that heat, in other words, facilitates the formation of these compounds (dioxins), if that is what you are arriving at.

Senator HART. What if some of this material is just put in the city dump and burned? Could that burning inadvertently produce dioxin?

Dr. VERRETT. I could only say that the likelihood is there; yes. Again, lack of actual experimentation does not give us any evidence or proof of this, but the fact is that these materials are formed when chlorophenols are subjected to heat and that would indicate to me that that is definitely a possibility.

Senator HART. What common products, or what common articles contain chlorophenol?

Dr. VERRETT. There are so many that I wouldn't be able to name all. But, every piece of newspaper or paper of any kind probably has chlorophenol used in the manufacture of paper. I am sorry I am not in an area which would enable me to give you total usage figures, but they are considerable.

This is washed out to some extent, but there probably are some chlorophenol residues, and paper would be one item and one which we can say is very widely used.

Another example-well, leather is cured by using chlorophenols in the tanning process. So leather materials contain it. There would be any number of other everyday items that would possibly have it. Senator HART. Well, just as I am reluctant to have pictures taken, I am reluctant to make these contrary statement and yet this one is not inappropriate.

If the materials that we customarily-and for generations, centuries I guess have been throwing into a fire contain chlorophenol, when you burn them, it is your opinion that dioxins can resultDr. VERRETT. Could possibly result; yes.

Senator HART. Is it possible that some of the birth defects for which there has been no medical explanation to date are the result of this kind of thing, where we have always done it and it has never seemed to hurt us?

Dr. VERRETT. I would say it is a possibility. It would be for others to assess this situation, but I think it is a distinct possibility because of the fact that these materials (chlorophenols) are ubiquitous, and if, in fact, chlorodioxins are formed in the environment, this is a possibility.

I should point out the studies done in mammals have been done by feeding, while the largest exposure may come from inhalation or dermal contact. That was the source of exposure occupationally to the tetrachlorodioxin. So here we have to be concerned not only about eating, but inhalation and perhaps contact exposure.

This brings up the subject of other materials. For example, we are also investigating

Senator HART. I was just going to say that it is hard to visualize a substitute for paper or leather, but can one have leather and paper without this material?

Dr. VERRETT. I would think so. I should point out some of the materials (chlorophenols) are washed out in the processing. The total amount used in the processing does not always remain in the products. I did not mean to imply that. That brings up another question: Are they washed out into the rivers et cetera?

Nevertheless, I am not really sufficiently knowledgeable of the technology to say whether something else could be substituted or not. Senator HART. Mr. Bickwit?

Mr. BICKWIT. I have heard several people criticize these chick embryo studies as being overly sensitive. I am not sure of this, but I believe the Secretary of HEW has criticized them.

Can you respond to that criticism?

Dr. VERRETT. Well, I have not as yet. As I mentioned in the testimony very briefly, this technique was started with just that idea, of finding a sensitive technique, if at all possible, for assessing toxic and also teratogenic response.

One of the great difficulties in all of the toxicology animal work, using mammals and primates, even, is the difficulty of relating, of course, to the human. There is perhaps another generation gap, if you can use that word, between the chicken or an avian species.

I would say without hesitation that these studies, for example, proved that this material is not for the birds, if I may phrase it that way. I would certainly not say that you can conclusively state that there is a human hazard from the results with the chick embryo.

However, inferentially we have evidence of that, and we have the inadvertent tie-in because of the chlorodioxin toxicity already known in primates and humans. I would certainly hope the human is less sensitive than the chick, but I feel what we really need, and I think that is pointed out very much by these hearings, is a very sensitive test, and then it remains to show this is not the case in the species more closely related to man.

I would rather demonstrate that something has an adverse effect in a sensitive system and then, by appropriate study, find out whether it will be relevant to man, than miss it altogether in an insensitive test. Although we do not try to make direct correlations, we feel certain anything seen in this system is worthy of further study, and I should also like to add we are trying to keep the study in the proper perspective.

That is, we use levels (doses) when possible that are relevant to the human exposure or other animal exposure and not simply try to produce effects with excessive amounts of material.

Mr. Brown. You state on page 4 that the most potent dioxin in the production of serious occupational hazards, seems to have been the tetradioxin.

What actual experimental evidence is there that suggests or confirms that tetra is the most potent of the dioxins?

Dr. Vekkert. You mean in animal work?

Mr. BICKWIT. Yes.

Dr. VERKETT. Of course the tests referred to earlier by Dr. Steinfeld show in that system that the tetradioxin is extremely potent in rate. I am not aware that the other dioxins have ever been studied. Mr. BICKWIT. Have the other dioxins ever been compared in potency in chick analysis?

Dr. VERKETT. Yes. As far as I know only in the chick embryos. Mr. BICKWIT. So, unless we can rely on the chick studies, we may be in very serious trouble, even more serious than it now appears on the basis of available evidence.

Dr. VERKETT. That is right.

Mr. BICKWIT. Are there any data available, either in mammalian studies or chick studies on the relative toxicity of dioxins compared to thalidomide?

Dr. VERRETT. If you used the chick as an exhibit or even the mammalian studies with the tetradioxine, which is the only one being studied at the moment, you would have to say this material is some 100,000 to a million times more potent in these particular species.

Now, I should add that the abnormal effects (terata) that we are seeing are not the same as we see with thalidomide, but the potential for producing abnormalties that we do find, it is of that order. Senator HART. Doctor, thank you very much. (The material referred to follows:)

BIBLIOGRAPHY

1. The Chick Edema Factor': Anon., Nutrition Reviews 26, 28 (1968). 2. 'Studies of the Chicken Edema Disease Factor': Friedman, L., Firestone, D., Horwitz, W., Banes, D., Anstead, M., and Shue, G., JAOAC 42, 129 (1959). 3. "The Occurrence of the Chick Pericardial Edema Factor in Some Oleic Acids and Products Therefrom': Ames, S. R., Swanson, W. J., Ludwig, M. I., and Brokaw, G. Y., J. Am. Oil Chemists Soc. 37, 10 (1960).

4. 'Studies of the Chick Edema Factor. II Isolation of a Toxic Substance': Yartzoff, A., Firestone, D., Banes, D., Horwitz, W., Friedman, L., and Nesheim, 8., J. Am. Oil Chemists Soc. 38, 60 (1961).

5. Collaborative Bioassay for Chick Edema Factor': Douglass, C. D., and Flick, D. F., JAOAC 44, 3 (1961).

6. 'Progress in the Chick Edema Problem': Friedman, L., Feedstuffs, March 17, 1962.

7. Occupational Intoxication Occurring in the Production of Chlorophenol Compounds': Bauer, H., Schulz, H., and Spiegelberg, U., Archiv fur Gewerbepathologie and Gewerbehygiene 18, 538 (1961).

8. 'A Technic for Testing Acnegenic Potency in Rabbits Applied to the Potent Acnegen, 2,3,7,8-Tetrachlorodibenzo-p-dioxin': Jones, E. L., and Krizek, H., J. Invest. Dermatol. 39, 511 (1962).

9. 'Studies of the Chick Edema Disease. 2. Preparation and Biological Effects of a Crystalline Chick Edema Factor Concentrate': Flick, D. F., Firestone, D., and Marliac, J. P., Poultry Science 44, 1214 (1965).

10. 'Chick Edema Factor: Application of Microcoulometric Gas Chromatography to Detection of Chick Edema Factor in Fats or Fatty Acids': Firestone,

D., Ibrahim, W., and Horwitz, W., JAOAC 46, 384 (1963); AOAC (1965) sections 26.087-26.096.

11. The Injection of Chemicals into the Fertile Eggs Prior to Incubation as a Toxicity Test': McLaughlin, J., Marliac, J. P., Verrett, M. J., Mutchler, M. K., and Fitzhugh, O. G., Tox, Appl. Pharm., 5, 760 (1963).

12. 'Use of the Chicken Embryo in the Assay of Aflatoxin Toxicity': Verrett, M. J., Marliac, J. P., and McLaughlin, J., JAOAC 47, 1003 (1964).

13. "The Role of Toxic Fat in the Production of Hydropercardium and Ascites in Chickens', Allen, J. R., Am. J. Vet. Res. 25, 1210 (1964).

14. 'Industrially Acquired Porphyria': Blieberg, J., Wallen, M., Brodkin, R., and Appelbaum, I., Arch. Derm. 89, 793 (1964).

15. 'Electron Microscopic Alterations in the Liver of Chickens Fed Toxic Fat': Allen, J. R., and Carstens, L. A., Lab. Inves. 15, 970 (1966).

16. 'Chick Edema Factor: Some Tissue Distribution Data and Toxicologic Effects in the Rat and Chick': Campbell, T. C., and Friedman, L., Proc. Soc. Exp. Biol. Med. 121, 1283 (1966).

17. 'Studies on the Metabolism of Chick Edema Factor: Distribution in Chick Tissue': Firestone, D., Higginbotham, G. R., Flick, D. F., and Ress, J., FDA Internal Preliminary Report, October 1966.

18. 'Light and Electron Microscopic Observations in Macaca mulatta Monkeys Fed Toxic Fat': Allen, J. R., and Carstens, L. A., Am. J. Vet. Res. 28, 1513 (1967).

19. 'Note on an Improved Cleanup Method for the Detection of Chick Edema Factor in Fats and Fatty Acids by Electron Capture Gas Chromatography': Neal, P., JAOAC 50, 1338 (1967).

20. 'Oils. Fats, and Waxes': Neal, P., JAOAC 51, 489 (1968).

21. 'Chemical and Toxicological Evaluations of Isolated and Synthetic Chloro Derivatives of Dibenzo-p-dioxin': Higginbotham, G. R., Huang, A., Firestone, D., Verrett, J., Ress, J., and Campbell, A. D., Nature 220, 702 (1968). 22. ‘Analysis of Commercial Chlorophenols for Trace Amounts of Their Condensation and Polymerization Products': Higginbotham, G. R., and Ress, J., FDA Internal Preliminary Report, November 1968.

23. The Identification and Crystal Structure of a Hydropercardium Producing Factor: 1,2,3,7,8,9-Hexachlorodibenzo-p-dioxin': Cantrell, J. S., Webb, N. C., and Mabis, A. J., Chem. Eng. News 45, No. 5, 10 (1967), and Acta Cryst. B25, 150 (1969).

24. 'Clinical Picture and Etiology of Chloracne': Schulz, K. H., Arbeitsmedizin-Sozialmedizin-Arbeitshygiene 3 (2): 25 (1968).

25. 'Report on Methodology for Chlorinated Aromatics in Fats, Oils, and Fatty Acids': Ress, J., Higginbotham, G. R., and Firestone, D., JAOAC, in press (1970).

26. Federal Register December 9, 1961, 26 F. R. 11828, 121.224; also Code of Federal Regulations, Title 21, sec. 121.1070. further amended Federal Register August 25, 1966, 31 F. R. 11215.

Dibenzo-p-dioxins

(Chick

27. Table: Embryotoxicity of Chlorophenols, Edema) FDA Preliminary Data, J. Verrett, 3/30/70. (Chick Embryos). 28. Table: Preliminary Report on Teratology Studies with Dioxin Using Golden Hamsters: FDA Preliminary Data, T. F. X. Collins, W. H. Hansen, and C. H. Williams.

29. Table: Preliminary Report on Teratology Studies with 2,4,5-T Samples Using Golden Hamsters: FDA Preliminary Data, T. F. X. Collins, W. H. Hansen, and C. H. Williams.

30. Letter: K. D. Courtney, NIEHS to J. McLaughlin, FDA, of 12/4/69 re Bionetics sample of 2,4,5,-T.

31. Letter: G. E. Lynn, Dow Chem. Co., to M. J. Verrett, FDA, of 2/9/70 re composition of Dow 2,4,5,-T sample.

32. Memo: FDA Internal from D. Firestone to A. D. Campbell, of 3/2/70 re composition of chlorinated Dibenzo-p-dioxin Standard.

33. Memo: FDA Internal from D. Firestone to A. D. Campbell, of 3/26/70 re samples for Chicken Embryo Testing.

34. Memo: FDA Internal from J. Ress to A. D. Campbell, of 3/26/70 re chlorophenol samples for Chicken Embryo Testing.

45-362 O 70-14

THE CHICK EDEMA FACTOR

1

A toric factor in some feed grade fats and fatty acids produces kpdropericardium and ascites in young chicks when 9 μ9. per kilogram body weight ore fed per day. There are a number of these toxic compounds, containing large amounts of chlorine. One has been characterized and synthesized.

In 1957, large numbers of chickens suffered from what appeared to be an epidemfe disease. Losses attributable to this epidemic have been estimated in the millions of dollars. The affected birds appeared droopy, showed ruffled feathers, and had difficulty breathing (L. Friedman, Feedstuffs, March 17, 1962).

In some flocks, over 50 per cent of the birds died with typical symptoms of the discase (V. L. Sanger et al., J. Am. Vet. Mcd. Assn. 133, 172 (1958)). When autopsied, the birds had pale hearts with hydropericardium, and livers that were pale, mottled, and had an irregular granular surface. In, the advanced stages, the abdomens were distended, and contained 100 to 500 ml. of clear, straw-colored fluid. The pericardial cavity is most susceptible to fluid accumulation, with the abdominal cavity next, and then subcutaneous tissue (D. F. Flick, C. D. Douglass, and L. Gallo, Poul-◄ try Sci. 42. 855 (1968)). The kidneys were pale and swollen: the fatty tissue of the gizzard was edematous; and the duodenum was swollen and soft (Sanger et al., loc. cit.). Hydropericardium was not as prominent in the older birds as in the broilers (Friedman, loc. cit.).

No acceptable explanation is available for the abnormalities associated with feeding the chick edema factor. Despite ac

cumulation of fluid in the pericardial and abdominal cavities of the affected birds, the hematocrit, blood volume, and moisture content of the heart, skeletal muscle, skin, and kidney were normal. However, the total body water content of the birds was signifi cantly increased. On the basis of these ob servations, it was suggested that the chick edema factor increased permeability of the cardiac vascular bed (Flick, Douglass, and Gallo, loc. cit.). Additional support for this hypothesis came from the finding that the toxic factor produced no appreciable change in the proportion or level of plasma proteins (Flick, D. Firestone, and J. P. Marliac, Poultry Sci. 44, 1214 (1965)).

The type of diet had a marked effect on the rate at which the chicks' bodies ac cumulated water. Chicks fed a natural grain ration containing 4 per cent toxic fat showed an increased body moisture content (78 versus 72 per cent for the controls) only at the end of the third week. Birds fed the same level of toxic fat in a semipurified diet showed a marked increase in body water content after seven days (79 versus 73 per cent) (Flick, Douglass, and Gallo, loc. cit.).

During 1958, a number of laboratories traced the disorder to the presence of a toxic substance in the unsaponifiable fraction of fats added to commercial poultry

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