Wm.B. Deichmann

What is there that is not poison? A study of the Third Defense by Paracelsus

University of Miami School of Medicine, 1931 South Bayshore Drive, Coconut Grove, Florida 33133, USA 2 Institute of Toxicology and Pharmacology, University of W/irzburg, Verbacher Strage 9, D-8700 W/irzburg, Federal Republic of Germany 3 Department of Toxicology, Karolinska Institute, Box 60208, S-10401 Stockholm 60, Sweden 4 Institute of History of Medicine, University of W/irzburg, K611ikerstral3e 6, D-8700 Wiirzburg, Federal Republic of Germany

Synergism among oral carcinogens. I. Results of the simultaneous feeding of four tumorigens to rats.

Abstract A mixture of four substances, namely, Aramite, methoxychlor, DDT, and thiourea was fed to rats at a level of 50 ppm of each in the diet for a period of 24 months. This dietary concentration is considerably below the tumorigenic dosage of each of the individual compounds. Compared to the control rats, a somewhat increased incidence of liver tumors was observed in the males, and to a lesser extent the females, given the combination of the compounds. The incidences of tumors at other sites in the control and treated groups were not markedly different. A second experiment was performed using a larger number of rats in which the same four compounds were fed individually as well as in combination, at a higher dietary level (80 ppm). In this experiment the incidence of tumors of all types in the rats fed the mixture of four tumorigens was no higher than that in the rats fed single tumorigens. No liver tumor was observed in any rat receiving any of these compounds. Thus, it would seem that these four compounds do not exert a synergistic or additive tumorigenic effect when fed to rats at the levels employed.

Human pesticide blood levels as a measure of body burden and pesticide exposure

Abstract Studies have been conducted on the variability and utility of whole blood and plasma organochlorine pesticide concentration measurements in man. Concentrations of p,p′-DDE, dieldrin, and β-hexachlorocyclohexane are remarkably consistent throughout the day. Minor increases in p,p′-DDE and p,p′-DDT serum concentrations were observed promptly following the ingestion of the evening meal. In random autopsy specimens, good correlations were found between blood and fat concentrations of p,p′-DDE, p,p′-DDT, and β-hexachlorocyclohexane (β-HCH). The concentrations of these insecticides in plasma, when measured in 5 individuals repeatedly throughout a work week, were also remarkably consistent. Plasma pesticide measurements are preferred to whole blood measurements. Compared to United States residents, markedly elevated blood concentrations of β-HCH were observed in graduate students and postdoctoral fellows who had come from Formosa and Japan. Apparently, concentrations of organochlorine pesticides in the blood are in equilibrium with those in the tissue and measurement constitutes a highly useful and readily obtainable means of estimating body burdens and exposure.

Blood levels of organochlorine pesticides in Argentina: occupationally and nonoccupationally exposed adults, children and newborn infants.

Abstract Determination of the concentration of organochlorine pesticides has been made in adults, children, newborn infants, and various groups of occupationally exposed individuals in Argentina. β-HCH levels in adults in Argentina are approximately 16 times higher, on the average, than the levels of β-HCH found in the U.S. In contrast, the concentrations of p,p′ -DDE, dieldrin, and p,p′ -DDT are closely similar to those in the U.S. Concentrations of β-HCH in children in Argentina are lower, but still higher than in adults in the U.S., and much higher than in U.S. children. Pesticide levels in workers handling HCH were extremely high, as were the levels of DDT and isomers in those occupationally exposed to this pesticide. No dieldrin was detected in these workers—a possible indication that microsomal stimulation by DDT may have been responsible for clearing the tissues. The DDE:DDT ratio appeared to be an accurate measurement of a recent exposure to DDT. Pesticides passed the placental barrier, but transmission was apparently somewhat retarded. Concentrations of p,p′ -DDE, p,p′ -DDT, dieldrin, and β-HCH in the newborn were approximately 40% of the pesticide concentration in the blood of the mother. This percentage was higher for α-HCH, and lindane.

Di-(4-aminophenyl)-methane (MDA): 4–7 year dog feeding study*

9 pure bred female beagles ingested purified or crude MDA (in 70 mg doses on 3 days of the week) over periods ranging from 3 years, 11 months to 7 years, 2 months. Total quantities of MDA ingested ranged from 39.98 g to 66.92 g/dog, or from approx. 4.0 to 6.26 g/kg body wt. Purified and crude MDA in the doses administered produced similar effects: (a)occasional loss of body weight followed by rather prompt recovery while treatment was interrupted; (b) no specific effect on blood sugar, BUN, creatinine, uric acid, total protein, albumin and a questionable effect on alkaline phosphatase activity; (c) from moderate to severe gross and micropathological changes in the liver, less severe effects in the kidneys and spleen, and occassionally gross or micropathological changes in other organs. Purified and crude MDA did not produce tumors of the urinary bladder or liver.

Retention of dieldrin and DDT in the tissues of dogs fed aldrin and DDT individually and as a mixture

Abstract Three groups of 6 adult male beagle dogs were fed aldrin 3 and/or DDT 4 by capsule on 5 days of the week for 10 months, as follows. Group 1: 0.6 mg/kg aldrin; group 2: 24 mg/kg DDT; and group 3: 0.3 mg/kg aldrin plus 12 mg/kg DDT. Group 4 served as control. After this feeding period the dogs were observed for an additional period of 12 months. Hyperexcitability and tremors were noted in some of the dogs treated with 0.6 mg/kg aldrin, and with 0.3 mg/kg aldrin plus 12 mg/kg DDT. There were no significant serum cholinesterase or aliesterase changes. The concentrations of dieldrin 5 in the fat, liver, and blood of the dogs were of similar magnitude for an individual tissue, whether the animals were treated with 0.6 mg/kg aldrin, or with the combined dosage of 0.3 mg/kg aldrin plus 12 mg/kg DDT. Retention of p,p′ -DDT and DDE in fat and blood was roughly 2.5–4 times greater after administration of 12 mg/kg DDT plus 0.3 mg/kg aldrin than after administration of 24 mg/kg DDT without aldrin. The concentrations of p,p′ -DDT and DDE in liver tissue were similar in both groups of animals.

EFFECT OF MICROWAVE RADIATION ON THE HEMOPOIETIC SYSTEM OF THE RAT.

Abstract Exposure of Osborne-Mendel, CFN, and Fischer strain rats to minimal doses of microwave radiation (24,000 megacycles) induced a significant leucocytosis, lymphocytosis, and neutrophilia after 7 hours of continuous exposure to 20 mw/cm2 with recovery in 1 week; 10 minutes of continuous exposure to 20 mw/cm2; and 3 hours of continuous exposure to 10 mw/cm2 with recovery in 2 days. Effects on erythrocytes, hemoglobin, and hematocrit differed in the three strains used. In Osborne-Mendel and CFN rats, all values increased; in Fischer rats, they decreased.

Effects of starvation in rats with elevated DDT and dieldrin tissue levels

SummaryWeanling, adult and old Osborne-Mendel strain rats were fed for 4 weeks diets supplemented with 50 ppm DDT, 7.5 ppm aldrin, or a combination of 50 ppm DDT plus 7.5 ppm aldrin. They were subsequently starved for 6 days, with free access to water. This period of starvation resulted in marked loss of body weight, marked loss of total body lipids, decreased liver-to-body-weight ratio, and a decreased total body-lipid-to-body-weight ratio.As a result of severe starvation, “total DDT” (simple summation of DDT, DDE and DDD) and dieldrin concentrations decreased in the blood of male and female rats of all ages, regardless of the pesticide supplement fed before starvation, but only in weanling male and female rats were reductions marked and statistically significant.There was no distinct pattern to the effects of starvation on the concentration and retention of pesticides in the brain and kidney of male and female rats of all ages.In general, in all rats, except for adult and old females, starvation induced a decrease in both the concentration and the total quantity of “total DDT” and dieldrin in the liver. In the two groups of females, the opposite occurred. Particularly in male rats, there was a marked conversion of DDT to DDD in the liver as a result of starvation.The total quantity of pesticides (DDT, DDE, DDD, dieldrin) in the total body decreased during the period of severe starvation, regardless of sex, age, or the pesticide supplement fed before starvation. On the whole, the effects were most marked in weanlings and least marked in old rats.In females of all ages, starvation induced from a moderate to a marked increase in the concentrations of DDT, its metabolites, and dieldrin in the abdominal fat. In male rats, “total DDT” increased, but dieldrin decreased in the abdominal fat. With the exception of weanling male rats, starvation increased hepatic microsomal enzyme activity for the substrates tested: EPN, p-nitroanisole and methyl orange.Feeding of the DDT and/or aldrin supplement for 4 weeks to male and female weanling rats resulted in a significant increase in growth rate above that of weanling rats fed the control diet.

Major metabolism and acute toxicity of aldrin, dieldrin, and endrin.

Abstract The photochemical isomerization and the fate of the cyclodiene pesticides—aldrin, dieldrin, and endrin—in mammals, plants, and soils was reviewed. Unfortunately, because of the many deficiencies in our knowledge, a precise statement in regard to the ecological implications of these pesticides in the quantities now employed is not possible at this time.

Dieldrin and DDT in the tissues of mice fed aldrin and DDT for seven generations.

Seven-Generation Study (P — F6): The concentration and total retention of dieldrin or p,p′-DDT and metabolites were determined in the total carcass of Swiss-Webster mice fed dietary supplements of aldrin 5 or 10 ppm, or DDT 100 ppm, to age 260 days.All groups showed a significant increase in total body retention (and concentration) of dieldrin or total DDT in the total carcass of the F1, F2, and F3 generations. Generally, these increases were related directly to increases in total body lipids, when compared with the P generations.The control (pesticide-free) diet was fed to all F4 generation experimentai mice from weaning to age 260. The pesticides absorbed by these animals while in utero and via lactation were found, at the time of sacrifice, to have been excreted completely.When the experimental diets were resumed with the weanlings of the F5 generations, a repetition of the general findings in the P and F1 generations was noted — demonstrating that pesticide retention and total body lipids are closely interrelated, and that a high body lipid content favors a high retention rate of these fat-soluble pesticides. These results support our earlier studies in rats (Deichmann et al., 1972) and investigations with cirrhotic human livers with severe fatty infiltration (Oloffs et al., 1974).Conception became more delayed with each succeeding generation, requiring some degree of “selective” breeding of the F4, F5, and F6 generations.ZusammenfassungSieben Generationen-Untersuchung (P — F6): Die Konzentrationen und Gesamtmengen von Dieldrin oder DDT wurden im ganzen Körper von Swiss-Webster Mäusen bestimmt, welche Aldrin 5 oder 10 ppm, oder DDT 100 ppm mit dem Futter einnahmen bis zum Alter von 260 Tagen.Alle Mäusegruppen zeigten eine erhöhte Ansammlung und erhöhte Konzentrationen von Dieldrin oder DDT im ganzen Körper der F1–F3 Generationen. Im allgemeinen liefen diese Erhöhungen parallel mit dem Körperfettgehalt.Alle behandelten F4 Generationen erhielten das pestizid-freie Kontrollfutter vom 21. Lebenstag an, bis sie das Alter von 260 Tagen erreichten. Die Pestizide, welche die Mäuse während ihrer Zeit in utero absorbierten und welche sie mit Muttermilch aufnahmen, waren am 260. Tage vollkommen ausgeschieden worden.Wenn die 21 Tage alten Tiere aller behandelten F5 Generationen wieder ihre Versuchsdiät bekamen, dann wiederholten sich die Ansammlungen und die erhöhten Konzentrationen der Pestizide im Körperfett. Diese Befunde zeigen, daß die Retention dieser Pestiziden und die Körperfettmenge eng miteinander verbunden sind, und daß ein hoher Körperfettgehalt die Ansammlung von fettlöslichen Pestiziden unterstützt. Diese Befunde bestätigen unsere früheren Resultate mit Ratten (Deichmann, et al., 1972), sowie Oloffs et al.s Befunde in menschlichen zirrhotischen Lebern mit starker Fettinfiltration (1974).Die Konzeption, besonders von der F4 Generation an, wurde mehr und mehr gehemmt, welches eine gewisse Auslese für die weitere Zucht erforderte.