W.E. MacDonald

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.

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.

Organochlorine pesticides and liver cancer deaths in the United States, 1930–1972☆

Abstract Animal studies have shown the liver to be the primary target organ following prolonged periods of absorption of toxic doses of organochlorine pesticides. Therefore, the core of our presentation is aimed at the liver. Since studies in our laboratory have been concerned primarily with DDT, aldrin, and dieldrin, these compounds are being given primary consideration.

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.

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.

CHRONIC TOXICITY STUDIES ON IRRADIATED BEEF STEW AND EVAPORATED MILK.

Abstract Beef stew (C-ration) and evaporated milk, irradiated at levels of 2.79 and 5.58 megarads were fed to rats and to dogs as 35% of their diets for a period of two years. Fat-soluble vitamins were administered separately to both species. Nonirradiated beef stew and evaporated milk of similar origin were used as the controls. Simultaneously, a breeding study was carried out in which the rats fed the irradiated foods were bred through four generations. A breeding experiment was also conducted on both rats and dogs. The urine of dogs was examined for protein casts and reducing substances. After two years of feeding, all animals were sacrificed and thorough histopathologic studies were performed on 24 tissues of each animal. No indication of any toxic effect due to the feeding of either irradiated food either in the longevity or the breeding phases of these experiments was obtained.

A study of the possible carcinogenicity of irradiated foods

Abstract An experiment was conducted in which male and female mice of four different strains, namely DBA, Swiss, C3H, and C57 black were fed for the duration of their life a mixture of foods (fruit compote, beef, tuna fish, sweet potato, and corn), all of which had been irradiated with 5.58 megarads of gamma radiation. A total of 2834 mice were used in the experiment. These mice were distributed at random, and divided equally, in two groups: one which was fed the irradiated diet, and one which received the control diet, identical in composition to the experimental diet except that is was not irradiated. At the death of these animals, each was subjected to a careful examination. All tumors found were examined histopathologically and were classified and tabulated according to type. Analysis of the tumor incidence of the mice fed the control diet and the mice fed the irradiated diet showed that there was no significant difference between the two groups. It is therefore concluded that gamma irradiation (5.58 megarads) of the foods used in this experiment did not render them carcinogenic for mice. An experiment such as this in which several strains of mice were used (some of which are known to be prone to develop certain types of cancer) is probably the best presently available method of testing a food intended for human consumption for carcinogenicity. Therefore, it would appear that irradiation sterilization with 5.58 megarads of gamma radiation does not increase the carcinogenic hazard of these types of food for men.

Organochlorine pesticides in the tissues of the great barracuda (Sphyraena barracuda) (Waldbaum)

The abdominal fat of adult barracuda caught in Florida waters was analyzed for organochlorine pesticides. Of a total of 281 fish, 63 % had 5 to 760 g abdominal fat. The fat of 96 % of these fish contained DDT or one of its isomers or metabolites. Except for the smallest and largest fish, the ratio of “total” DDT in fat to kg body weight remained constant (0.08 to 0.11 mg/kg). During the spawning season, in addition to fat, certain organs and tissues of these fish were also analyzed. The highest pesticide concentrations were found in the fat. Assigning to the concentration of “total” DDT in abdominal fat a value of 10, the rating for the concentration of “total” DDT in the liver becomes approximately 1.1, in the pyloric cecum 1, in flesh 0.7, and for the fully developed gonads 0.5. It seems unlikely that larval barracuda are affected unfavorably by these low concentrations of DDT unless they are exceedingly sensitive to this compound. Since the quantity of abdominal fat and tissue pesticide concentrations were highest at the beginning and lowest during the height and end of the spawning season (and if this should apply to other fish species), then it can be concluded that spot-checking fish tissues for pesticides once or twice a year, more likely than not, provides misleading information with regard to pollution. Tissues and flesh of all barracuda were fed to cats, with no symptoms of ciguatera.ZusammenfassungDas Bauchfett ausgewachsener Barracudas (Pfeilhecht), die an der Küste Floridas gefangen wurden, wurde auf Pestizide aus der Gruppe der chlorierten Kohlenwasserstoffe untersucht. Aus einer Gesamtzahl von 281 Fischen enthielten 63 % zwischen 5 g und 760 g Bauchfett. Das Fett von 96 % dieser Fische enthielt DDT oder eines seiner Isomeren oder Metaboliten. Mit Ausnahme der kleinsten und der größten Fische blieb das Verhältnis von „Gesamt-DDT“ im Fett zum Körpergewicht konstant (0,08 bis 0,11 mg/kg).Während der Laichzeit wurden zusätzlich zum Fett bestimmte Organe und Gewebe dieser Fische untersucht. Die höchsten Pestizid-Konzentrationen wurden im Fett gefunden. Ordnet man der Konzentration an „Gesamt-DDT“ im Bauchfett einen Wert von 10 zu, so sind die Vergleichszahlen für die Konzentrationen an „Gesamt-DDT“ in der Leber annähernd 1,1, in den Pylorusanhängen 1,0, im Fleisch 0,7 und in den voll entwickelten Gonaden 0,5. Es ist unwahrscheinlich, daß diese niedrigen DDT-Konzentrationen ungünstige Wirkungen auf Barracuda-Larven haben, sofern diese nicht eine außergewöhnliche Empfindlichkeit aufweisen.Die Menge des Bauchfetts und die Pestizid-Konzentrationen im Gewebe ist zu Beginn der Laichzeit am höchsten, auf dem Höhepunkt und am Ende derselben aber am niedrigsten. Falls dieses auch für andere Fisch-Species gilt, ist anzunehmen, daß die Entnahme von Stichproben zur Bestimmung von Pestiziden in Fisch-geweben ein- oder zweimal im Jahr zu irreführenden Ergebnissen hinsichtlich der Umweltverschmutzung führt.Fleisch und Gewebe aller Barracudas wurden an Katzen verfüttert, ohne daß Symptome einer Vergiftung (mit Ciguatoxin) auftraten.

The chronic toxicity of octadecylamine in the rat--a supplemental report.

Abstract Rats fed diets containing octadecylamine at levels of 200 and 500 ppm, respectively, for a two-year period exhibited no signs of toxicity and no pathologic changes attributable to the feeding of this compound. Food consumption, increase in body weight, and rate of survival of the rats were normal. These results confirm the conclusions of our previous report.