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carry another dissolved chemical through cell walls, that otherwise might not have been crossed by the chemical without the DMSO. . Using a test where cancer was induced in mice by subdural implantation of methyl-cholanthrene crystals, E.R.Laws (in a manuscript submitted to EPA on May 13, 1970) reported that cells from this cancer could be transplanted by injection of a saline suspension of cells into other mice. He also reported that visual tumors developed in 10 to 18 days, with subsequent relentless growth and eventual death of the mice as the normal consequence. DDT administered at 5.5 mg/Kg/day gave preliminary evidence of prolonging the life of the treated and challenged animals. There was some suggestion that DDT had an adverse effect on the Sodium-Potassium-stimulated ATPase in the tumor, and an alternative suggestion was that DDT might have a^general subliminal toxic effect an the whole animal" which could make it a less suitable host for the transplanted tumor. A paper by R.P.H. Thompson et al.,1969. (Lancet II (7161):4-6, July 5, 1969) explains how DDT was administered to a 17 year old boy for control of unconjugated juvenile jaundice. This treatment replaced phenobarbitone which had been used earlier. The mechanism suggested for the successful therapy was the induction of liver microsomal enzymes, which resulted in reduced plasma bilirubin levels. The treatment resulted in producing an elevated plasma DDT level, and for 7 months after the end of DDT therapy, his biliruben level had remained low. The authors reported no side effects were noticed, there was no proteinuria, and other liver function tests and routine haematological tests remained normal. A paper by Hazeltine in 1971 (Clinical Toxicol. 4:55-61), looked at the Literature for evidence about DDT residues in people Living in Agricultural areas, and the possible impact this chemical and other agricultural chemicals might have on juvenile jaundice. The conclusions I drew were that DDT appeared to be present in significant (+therapeutic) levels in the body fat of people living in this area, that the observed infants who were breast fed and had a reduced incidence of jaundice, could be explained by the effects of this residue. There were other interesting parts to this literature review, such as the competitive or counteracting effect on liver enzyme induction by DDT, attributed to exposure to the pesticide Malathion. " - The competitive or antidotal effect of DDT and barbiturates was the basis for hospital emergency room treatment of attempted barbiturtate suicide cases with injected DDT. (Richard Rappolt Sr.,M.D., personal communication) Dr. Rappolt treated at least two patients with DDT dissolved in peanut oil; both patients were reported ambulatory and went home the next day. This therapy evolved from the understanding of veterinary practitioners who use barbiturates to antidote animals that have organochlorine pesticide poisoning. Apparently the competitive antidotal action explains the speed of effect, which is too fast for enzyme induction and metabolism of the excess chemical. It was also interesting and sad to see Dr. Rappolt dismissed from the hospital emergency room where he practiced for reasons that appeared political. The published newspaper story explained that he was dismissed for experimenting on people with DDT; his reply was that a good emergency room physician must be ready for all kinds of unusual situations.

Iz Finally, while not directly dealing with cancer testing,'but still bearing on the rat liver enzyme induction issue, two papers should be mentioned. These are P.R.Datta 1970, and Datta and Nelson, 1970 (Industrial Med. 39:190-94 and 195-98). These papers report on a study in which carbon 14 DDT and its metabolites were applied to perfused rat liver and kidney slices, with the rate and metabolite production recorded. The experiment was well quantified by accounting for the total radioactivity. Each step of the metabolic process was confirmed by synthesizing the molecules and applying each one to confirm the entire process. Keep in mind that this was an in-vitro study and there was no fat sink to preferentially adsorb (selectively partition) the highly lipid soluble molecules, as would occur in a living rat. These workers showed that the metabolism proceeded from DDT to DDA, a water soluble metabolic product. The rats used in this test were preconditioned with DDT for three days prior to the use of their tissues. These authors reported that the first roughly two-thirds of the metabolism occurred in the liver, and the last third in the kidney. The rates of metabolism were found to be quite rapid in this isolated tissue system. The alleged persistent DDT metabolite in nature (DDE) was degraded to DDA, with 14.5X of the DDE converted to DDA in 24 hours in untreated (unconditioned) animals, and 23.8% found as DDA after 12 hours in rats which had been conditioned for 3 days with DDT. Susmary In response to the format proposed for this Seminar, and looking for significant correlations between forecasts and the facts available today, it appears that the suggestions and predictions made in the 1970s about DDT as a human carcinogen were only strawmen which have failed to occur. The data from a number of studies showing some alleged adverse effects in mice fed at maximum tolerated doses of DDT for lifetimes (more or less) is suggestive but extremely difficult to interpret. At the same time, there is evidence to refute the hypothesis that DDT is a human carcinogen. These conflicts appear to occur for a number of reasons. Some of these reasons are: 1. The choice of inappropriate test species and protocols to evaluate DDT as a carcinogen, has led to a diversity of conflicting results. High doses of DDT have seemed to produce random physiological effects, but these conflicting data have had the tendency of making the whole process of dose-response evaluations of the data for cancers remote, if not - impossible. . 2. There is no clear data for the doses correlated with cancer production in mice treated with large doses of DDT, in the literature I have reviewed for this seminar. This suggests that DDT is not causally related to the adverse conditions seen in the test mice, so other explanations should be sought to explain the abnormal pathology which is described. 3. People who work in "pure research" do not seem to be interested in getting into the political arena, where their research findings may be expected to be made to fit into some social framework, or to support some I cause. 4. Extrapolations of data that may provide some meaningful insights may also involve some risk of being wrong. Therefore such extrapolations 2502146198

are usually avoided by "pure research" workers, and left to the "apocalyptics", who do not seem to care much about accuracy or integrity. 5. Positive data on anticarcinogenic and therapeutic effects of DDT are generally neglected, when looking at dose-response data. Most researchers are looking for harmful effects. Society does not reward findings of no harm. 6. There is a strong tendency to neglect the unprovable, such as the evidence on improved vigor and increased life span for the human population, which has been exposed to low levels of DDT for many years. 7. We need to examine the idea that a potential or weak organic chemical carcinogen can also act in a way analogous to a therapeutic agent at non-carcinogenic doses, to show beneficial actions within a dose-response relationship. If there are both beneficial effects at low dose, and harmful effects such as carcinogenicity at high dose, from the same chemical molecule, then it could be appropriate to label a carcinogen as beneficial. Selenium, the inorganic element may to provide a model for this kind of thinking. 8. In any carcinogenic testing experiment, the most important question concerns what is the highest dose which the test animal can tolerate without loss of normal physiological body system functions. Doses which cause loss of homeostasis are not expected to show reproducible dose-response effects at any particular target site. This high dose loss of homeostasis is the most reasonable way to interpret the alleged DDT mouse cancer test data reviewed for this report.

GROUP x 1 2 3 ~~Z~z~~ - 4- ~~a+ -5• _ e;l y:<s:_~ x 6 ~s~~~- ~ s~ 3F ~Gi Diet ' Stock . Pu rified - 1 2 3 4 5. 6 x Protein Lu1nuu uvUiUtlcuG- Ulelu;AlhD CD-I7:1ICE E 5 /l . s~. •• t(3-]2 mice necropsie:flsxlgraupl l~Gmc:i PERCENTAGE \YttH TUMORS - MULTIPLE LYMPHOMA- - ANYTUMOR TUMORS LEU:EfdIIA LUNG. HEPATOMAS irASCULAI; MALES ' .67 • 33 33 28 17 17 .57 7 • -94 29 • 7 • 0•• 56' 13 ' 13 13 . ' 6_ 13 • 50 • 14 14 28 0 .:14 • 21 0 5 5 t5 • 0 r 72 16 • • 22 44 ~6 6 . FEMALES . as 30 • 50 30 0.. 0 73 7 '7 60 0 • 0 • ' 69 23 15 23 ' 0• 15 • 67 - 20 . 13 .33. 7- ' 13 17 35 - 24 ` 0• ' 6 82• ?3 5o • -23 .. . 0 , , : 18 •: Number of mice x killed at and at 9:of survivors Fat 80-tveek study with liver no3ules .1NC1 55; 37„ 1975. 26.3 2Z7 M 276 260 • lot 121' - 8roup No. at Mice• Feeding+ Total Tumours by 18 • months . Liver Tumours Lung Tumours• Lympho- .- Reticular Neoplasms • OiheP Neoptasms . 1- 40 4g. dietlday 4 1.. . 1 2• D• I mouselcage • • . 2 40 -1j. diet/day 4•' 2-- • 0• • •1 1 testis I mouselwge - '3- 40 Diet ad libitum 32 • 15' 2 11 • 2 testis 1 mouselcage ' - • L kidney I I thyroid •6 40 Oiet sd libitumX 23 • 8 " 6 9' , 0 5 micelcage • ~• Autbred Swiss albino males maintained under SPF Conditions +'5iandar.dpeileteddiet ' • x 5.83. dictlday . N ~ 0 N ~ A W N O O