Comparative toxicology of N-nitroso compounds and their carcinogenic potential to man.
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Biomedical subjects
Publications and source records attributed to F Coulston.
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Mirex was fed at levels of 1, 5, 15, and 30 ppm to mice, 5 and 30 ppm to rats, while monkeys received the chemical by stomach tube at levels of 0.25 and 1 mg/kg (equal to 5 and 20 ppm). Mice were killed and their livers obtained at 2, 4, 6, 9, 10, 15 and 18 months, whereas rats were killed and surgical biopsies were taken at 16, 19, 26, and 36 months. Cytochemical techniques were employed to detect activities of lysosomal beta-glycerol phosphatase (ACpase) and glucose 6-phosphatase (G-6-pase). ACpase and G-6-pase remained unchanged and comparable to controls in livers of mice receiving 1 ppm. G-6-pase decreased in centrilobular areas while ACpase increased with time in the higher groups. At 12 months, liver cells that lost their G-6-pase activity surrounded by Kupffer cells that contained strong ACpase. In contrast, rat livers had no increase in ACpase and little loss in G-6-pase. Surprisingly, and in spite of the high levels of mirex ingested, monkey livers showed no loss of G-6-pase or activation of ACpase. Ultrastructurally, the underlying feature in all livers was proliferation of smooth endoplasmic reticulum (SER) displaying species variation. Thus, in mice, intense proliferation of SER that was both time- and dose-dependent was localized in specific regions of the cytosol. Hepatic cells, damaged and necrotic in mice fed 5, 15, and 30 ppm, were phagocytosed by activated Kupffer cells. SER proliferation in rat and monkey liver cells was less conspicuous than in mice. Except for this change, rat and monkey liver cells were normal. There studies emphasize species and enzyme variations in response to mirex. An interesting aspect observed was the lack of lysosomal catabolism during liver enlargement.
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Similarities between reproductive processes in humans and chimpanzees have led to speculation that the chimpanzee might be an excellent reproductive-endocrine model of humans. Data comparing patterns and concentrations of serum gonadotropins, prolactin, and sex steroids in female humans, chimpanzees, and rhesus monkeys sustain this concept. The striking evidence that levels of estrone, estradiol, estriol, progesterone, and chorionic gonadotropin are similar during human and chimpanzee pregnancy support the contention that chimpanzees, like humans but unlike rhesus monkeys, have a definitive fetoplacental unit. Likewise, during normal menstrual cycles serum patterns of LH, FSH, progesterone, and estradiol are similar in women and chimpanzees, but differ in rhesus monkeys. Thus by using the chimpanzee it may be possible to accurately assess the safety for human use of compounds that might affect reproductive-endocrine processes without direct exposure to humans.
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Fertility in a rhesus monkey breeding colony was significantly increased by caging females with males immediately after detection of the preovulatory luteinizing hormone (LH) surge. LH was measured in daily serum samples by a rapid (24-hr) radioimmunoassay which used iodinated ovine LK as tracer and an antiserum to human LH.
The principal types of hormonal agents used in the production of meat for human consumption are estrogens, progestagens, and androgens. Only the last class is truly anabolic. Each type of compound named above has fairly characteristic toxic effects after prolonged intake. In this review, an attempt will be made to relate available information from experience with the administration of these three types of hormones to humans to the question whether sufficient amounts of these chemicals can remain in meat cut from carcasses of animals administered hormones during finishing to have deletarious effects on human ingesters. Present indications are that administration of stilbestrol to pregnant women may result in a somewhat increased incidence of cervical and vaginal cancers in their daughters; such administration appears to have no effect on the incidence of cancers in sons and only slight, if any, effect on that in the mothers. Other estrogens seem to have no specific effects on the incidence of cancer. Progestagens also are not known to induce any specific lesions. Although many androgens are known to produce edema, fever, and jaundice, they have not been found to cause specific lesions to any significant extent. With reference to stilbestrol, the doses given to the mothers of affected children have ranged between 5 and 125 mg/day. Because muscle, liver, and kidney from steers treated with stilbestrol in the usual way (s. c. implantation of a pellet at the base of an ear) have been found to contain less than 0.5 ppb of stilbestrol one month after implantation of the pellet, it is obvious that, to approach even the lowest clinically used dose of stilbestrol, a person would have to eat daily a quantity of such animal products that would be impossible to ingest. The findings that a mean of 26.4% of an oral dose of stilbestrol is excreted within 24 hours and that 99.5% is excreted within a week indicate that cumulation of this chemical within the body from the low level of intake provided by meats is not likely to reach a significant level. This would be so even though the animal product contained more than the 0.5 ppb mentioned above.
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