Zur Toxikologie von Zusatzstoffen und Rückständen in Nahrungsmitteln.

The content in foodstuffs of residues of chemicals, pesticides, heavy metals, mycotoxins, medicinal agents, and also food additives is so small that acute or chronic intoxication is, in general, not to be expected. The determination of the permissible maximal quantities and analyses of the food by the competent authorities, that still needs to be on a wider scale, should assure that in the foreseeable future no damage to health need be feared. Nevertheless, there is certainly no room for complacency, as possible physiological and toxicological action of small quantities of single, or of several, noxae to which we may be exposed over many years, may exist, and we know little about them. There is, therefore, no possibility of laying down a definite threshold value of innocuity. This applies in particular to the presence of small quantities of cancerogenic substances in the food or the use of nitrites for the preservation of meat. This problem can be solved only by further animal experiments and epidemiological researches. Furthermore, it must be constantly borne in mind that most of the residues that are found in foodstuffs, such as pesticides or heavy metals, can, in high doses, cause acute intoxications; and poisonings of humans are the consequence of pollution of food or drinking water by accident or negligence. Itai-itai disease, minimata disease or sudden death of fish after chemicals have got into streams are examples of chronic or acute toxicity. The fact that humans are often exposed to such toxic substances in toxic quantities, not directly but only after the use of additives raises difficulties for the timely recognition of the danger and the tracing of the cause

Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cold-adapted rats.

The toxicity of 60μg/kg 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) given IP in corn oil/5% acetone was examined in male Sprague-Dawley rats adapted to 25 °C or 4 °C ambient temperature. Cold exposure significantly reduced mean time to death and tended to increase mortality. Body weight at the time of death was reduced at both ambient temperatures to about the same extent. Thus, the rate of body weight loss was about twice as fast in nonsurvivors at 4°C than at 25 °C. There was a continuous decrease in feed intake of the non-survivors at 25 °C until death. However, no reduction in feed intake occurred in any of the rats at 4 °C ambient temperature. At 14 days after dosing all TCDD-dosed animals were hypothyroid in terms of T4 but essentially euthyroid in terms of T3. Oxygen consumption at 10 days after dosing was reduced to the same extent in all TCDD-dosed rats without regard to survival status. By day 20 after TCDD dosage, survivors increased their oxygen consumption at both ambient temperatures to nearly control levels whereas non-survivors were unable to do so. Body temperature of all animals remained within normal range except for the non-survivors, which showed reduced rectal temperature shortly before death. It is concluded (1) that cold adaptation aggravates the toxicity of TCDD, (2) that reduced feed intake alone cannot explain TCDD-induced wasting syndrome, (3) that reduced oxygen consumption in TCDD-treated rats may be due to reduced feed intake and/or altered thyroid hormone status, and (4) that TCDD is likely to activate metabolic pathways which represent a wasteful utilization of ingested and/or stored energy

Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats.

The hepatocarcinogenic effect of Clophen A 30 and Clophen A 60 was tested in male weanling rats by long-term feeding over a period of 832 days. The mortality rate was investigated in 100-day intervals. In the first 800 days liver carcinoma accounted for 21% of necropsies in the Clophen A 60 group but only 2% of the necropsies in the Clophen A 30 group and none in the control animals. The tumors were first observed after 700 days. After 800 days hepatocellular carcinoma was the most common lesion observed in the Clophen A 60 animals (61%) whereas it was only observed in 3% of animals in the Clophen A 30 group and 2% in the controls. Preneoplastic lesions, such as foci of hepatocellular alterations and neoplastic nodules, were first observed after Day 500. The incidence of foci predominated in all time intervals, but an increase in neoplastic nodules and hepatocellular carcinomas was observed with increased time. There was a marked trend from foci to neoplastic nodule to hepatocellular carcinoma with time. The total mortality rate and the incidence of thymoma, inflammatory lesions of the urogenital tract, in the experiment were significantly reduced by Clophen administration. Whether this protective effect could be induced by polychlorinated biphenyls (PCBs) is discussed

Inhibition of intercellular communication of rat hepatocytes by nafenopin: Involvement of protein kinase C.

Peroxisome proliferators (PPs) have been shown to cause tumours in rodent liver. The mechanism of action of these chemicals is only poorly understood. Current evidence, however, suggests that they may cause tumours through a tumour promoting activity. In the present study we therefore evaluated the effect of three peroxisome proliferators on gap junctional intercellular communication (IC) of cultured hepatocytes. Interference with IC is thought to be one of the mechanisms involved in tumour promotion. IC was detected by dye coupling of hepatocytes using microinjection of Lucifer Yellow CH. Five hours after plating, coupling of the cells amounted to ~90%. Incubation of hepatocytes with the PPs mono(2-ethylhexyl)phthalate (MEHP), nafenopin and [4-chloro-6-(2,3- xylidino)-2-pyrimidylthio]acetic acid (Wy-14,643) decreased dye coupling of the hepatocytes. Half maximal effects were obtained at ~50 μM nafenopin, 150 μM Wy-14,643 and 200 μM MEHP. Addition of the specific inhibitor of Ca22+-dependent protein kinase C isoenzymes, Go 6976 (2 μM) prevented inhibition of IC by nafenopin, but not by the two other peroxisome proliferators. Further studies suggest significant differences in the mechanisms underlying inhibition of dye coupling between hepatocytes by nafenopin and by phenobarbital, a known tumour promoter in the liver. The results show that the PPs nafenopin, MEHP and Wy-14,643 decrease IC between cultured hepatocytes. Inhibition of IC by nafenopin, but not by MEHP and Wy-14,643, is most likely mediated by Ca2+-dependent protein kinase C isoenzymes

Short-term studies with the cryptating agent hexaoxa-diaza-bicyclo-hexacosane in rats.

In short-term experiments rats received single doses of 50, 100, and 500 μmoles/kg of the cryptating agent A 222. A dose-related increase in the activities of GOT and GPT in the serum was observed 6 h after treatment, reaching values up to 11 and 3 times that of the controls, respectively. However, the enzyme activities returned to the control levels within 3 days. The activity of alkaline phosphatase and the levels of protein and cholesterol in serum were not altered during the observation period of 7 days. Histopathological examinations did not show any changes in the liver, kidney, heart, lung, thymus, spleen, or intestine. The elevations of GOT and GPT seem to be due to a transient liver lesion, since no histopathological alterations of the liver became apparent. These results show that after single applications of A 222 at all doses used, no severe lesions occur in the observed organs

Stimulation of nonbiliary, intestinal excretion of hexachlorobenzene in rhesus monkeys by mineral oil.

Four rhesus monkeys were administered various doses of hexachlorobenzene (HCB) po, to achieve widely varying adipose tissue levels. One month later, each animal was provided with a bile duct bypass allowing for interruption of the enterohepatic circulation (EHC). Effects of mineral oil-supplemented diet and/or interruption of the EHC on urinary, biliary, and fecal excretion of HCB and its metabolites were quantified. Urinary excretion of HCB was not affected by mineral oil but was reduced 20 to 60% by interruption of the EHC. Similarly, biliary excretion of HCB was also reduced 25 to 60% by interruption of the EHC and was not altered by mineral oil. Fecal excretion was increased about fivefold by mineral oil, whereas interruption of the EHC had no effect on the amount of HCB in feces. Results demonstrate that interruption of the EHC reduced urinary and biliary excretion of HCB metabolites, whereas mineral oil specifically stimulated intestinal excretion of the parent compound

Enhanced intestinal excretion of hexachlorobenzene in rats by intraluminal injection of hexadecane.

The effect of hexadecane on the intestinal excretion of hexachlorobenzene was studied in female Sprague-Dawley rats dosed twice with 14C-hexachlorobenzene at 50 mg kg-1 per os. Injection of 75 mg n-hexadecane into ligated and unligated segments of the intestine increased concentrations of hexachlorobenzene in intestinal contents by about two- or three-fold in jejunal and ileal segments, and about two-fold in the cecal-colon segment. The jejunum appeared to be the site of greatest excretion of hexachlorobenzene, followed by the ileum, the cecum and the colon. This order is opposite to our previous data from animals with an undistributed intestinal passage. The apparently greater excretion of hexachlorobenzene into the small intestine is probably due to its much larger surface area than that of the large intestine. However, the residency time of luminal contents in the large intestine normally exceeds that in the small intestine by about 20-40-fold, which apparently more than compensates for the difference in relative surface area between small and large intestine. Thus, residency time appears to be a more important factor than surface area in determining the intestinal elimination of hexachlorobenzene. These results with hexachlorobenzene are probably typical of physiological disposition of lipophilic halogenated hydrocarbons generally