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-(O She also points out that chemical carcinogens are dose related snd quite site specific. Furthermore, low doses and high or "heroic " doses may not act the same way in test animals. She says at page 131: This use of heroic doses is accepted without question by regulatory agencies despite its acknowledged pitfalls, while the public is generally unaware that such pitfalls exist. The pitfalls derive from the fact that the biochemical fate of very small doses of a chemical is usually not the same as that for large doses. The differences that chemicals display between their acute and chronic toxicities is testimony to the fact. Smaii doses of a chemical may follow metabolic pathways that does not convert it into a carcinogen, but with increasing doses the pathway becomes saturated and the excess chemical is diverted to a new pathway that does convert it to a carcinogen. Or, small doses of the chemical may be prevented from exerting carcinogenic activity be combination with a biochemical normally present in the body. If the supply of the biochemical is expended by the large doses, the excess chemical is then free to exert its carcinogenic effect. In considering the beneficial effects, such as the apparent prevention of cancers, there may be a whole group of physiological activitites working in concert. There are some studies which I want to call to your attention, particularly because they seem to refute the idea that DDT in test animals will result in adverse effects. K. C. Salinskas and A. B.Okey, 1975 (J. Nat, Cancer Inst.55:653-57) predosed Sprague-Dawley Rats with diets containing either 100 ppm of DDT and or 250 ppn of Halathion, for 14 days. Beginning on day 50 following the conditioning, these rats were dosed daily by stomach tube for 21 consecutive days with 0.714 mg. of dimeythylbenzanthracene (DMBA), a known carcinogen. These animals were sacrificed 230 days following the start of the DMSA treatment. The DDT treatment reduced the incidence of rats with leukemia and mammary tumors, and no deaths occurred with the DIrT treated rats until the time of autopsy. The significance of the absence of tumors in rats treated with DDT was greater than .001. The authors speculate that the DDT caused increase hepatic enzyme activity, causing increased metabolism and excretion of the DMBA> E. t4. Walker et a1.1970 (Indust. lied. 39( 7) :60) administered DDT in dimethyl sulfoxide (DMSO) 4 to 6 days I.P.to mice which had Ehrlich ascites carcinomas. The note I saw was short, and the reason for mentioning this reported inhibition of tumor development was to comment on the use of DMS9 as a carrier. The same solvent was used with DDT in part of the Bionetics Study, which was looking for, but not finding evidence of Teratogenicity in mice when DDT in flriSO was administered sub-cutaneously. When I received the document which contained the report of this study, I wrote to the National Institute of Health and asked about this use of TMSO. 7ne NIH response was that ahISO alone was tolerated without teratogenisis in the types of mice under test. The concern I have is that in those pesticides where there was some reported adverse effects, the coupling effect of IMSO could cause greater than simple additive effect. In live animal tests, the the cell walls might be crossed faster with a solvent such as DMSO, because of its alleged capacity to penetrate cells and its solvency which could 25Q1171312

.AA 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.E.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 prel-iminary 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 on the whole animal" which could make it a less suitable host for the transplanted tumor. A paper by lt.P.H. Thompson et al.,1969. (Lancet II (7161):4-6, July 5, 1969) explains how DD'T 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 Di'fT 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 no rmal. 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 DIYT 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. 4

1Z , Finally, while not directly dealing with cancer testing,- but still bearing on the rat liver enzyme induction issue, two papers should be mentioned. 'Lliese are i'. R. Datta 1970, and Datta and Nelson, 1970 (Industrial Med. 39:190-94 and 195-98). These pape rs 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. tGeep 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 DDrT 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. lhese 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 inetabolism were found to be quite rapid in this isolated tissue system. The alleged persistent DDT metabolite in nature (DDE) was degraded to DDA, with 14.5% 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 DiyT. Summary 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. Th e choice of inappropriate test species and protocols to evaluate DDT as a carcinogen, has led to a diversity of conflicting results. High doses of DD'T 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 no t 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 describe d. 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 cause. 4. Extrapolations of data that may provide some meaningful insights may also involve some risk of being wrong. Therefore such extrapolations 2501171314

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 DD'f 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.

TUMOR iNCIDEI~CF- IJNT~:E~ITED CD-1 ffilCE •• t13 ;22 mice netrapsi~/sexlgroupl PERCENTAGE WITH TUMORS , '6"° ~ F '~s ' ec'~ s;:~:ea~^' . GROUP MULTI PLE LYMPNOMA- ANY TUMOR TUMORS LEUR0M1A MALES . x ! • .67 • 33 33 . 2. . 57 . , 7 ••14 . • • 3 , 56 • ' 13 ' 13 ' • 50 ' 14 14 -- 5 21 0 5 ~( 6 ~ 72 . 16 • • 22 • Ff'MALES ' _- .. 30 • 50 2 7 7 3 . ~ • •• 23 15 4 . • ~ • 13 ~ ~ . 17~ 35• 6 • ~ : . 23 50• ~ Number of mice x x killed at end of %of survivors Diet ' Protein Fat SO-tveelc study with liver nodules ~ • M. f .. . M F ...__... ~.: Stock = 26.3 4.5 276 260 . • 12 [3• PurifiK 22.7 11.3 101 121• _ 39 , 64 ' ES-4.s~eccl l ~ nc ~t ! 41s LUNG. HEPIi^ 70MAS I~ASCl1LAlZ ' 28 ;• 17 17 ' 29 ' 7• 0.• 0 6 • 13 28' 0 ~ .';14 5 5• •• 0 44 ~6 • 6 • 30 t? •. 0 . 60 ' fl• ~ a. 23 • 0•. • 15 .33. 7• 13 24 0•. ~ ' 6; 23 „ . 0 !8'. . .iNC! 55,• 31,, 1975. Z roup No, of Mice• Feeding} ToW Tumours by 18 months . Liver ' Tumours Lung Tumours Lympho- .• Reticular Neoplasms • ' Other Neoplasms • 1' 40 4g. diet/day 4 i. I • 2.. D• . , 1 mouselcaga .2 '• • 40 5g. diet/day • , 4; ' • 2 • • . 0. 1 #esiis • . I movselcage • • • . . ,' - • :3' 40 Diet ad libitumX 32 15' 2 11 • • 2 tesiis • . I mouse/cage t kidney ' j I thyroid .4 40 Diet b iibitumx 23, ' • 8 ` 6 0 . 5 mice/cage • ' . 1 • Auibred S:,jiss albino males mainialried under SPF Conditions • +' S;fandard pelleted diet x 3.8g. diettday . •