Embryotoxicity and mutagenicity of mycotoxins.

Embryotoxicity: Aflatoxin B1 (AFB1), G1 (AFG1), and Patulin (PA) were investigated in NMRI mice for embryotoxic and teratogenic activity. These three mycotoxins were injected intraperitoneally or given orally on day 12 and 13 of pregnancy. AFB1 (15, 45, and 90 mg/kg ip or 45 mg/kg po) produced moderate retardation in fetal development and a dose-related increase of cleft palates, wavy ribs, and diaphragm changes. The effects after injection of AFG1 (45 to 90 mg/kg ip) were reduction of fetal weights, increase of diaphragm changes, and malformations of kidneys. PA (1, 25, 2, 5, and 3.75 mg/kg ip or 3.75 mg/kg po) was found to elevate the rate of cleft palates after 3.75 mg/kg. Dominant lethal assay: Neither PA (2, 5, and 5 mg/kg ip) nor AFB1 (15 and 45 mg/kg ip) increased the frequency of the dominant lethal mutations. Both mycotoxins showed no mutagenic activity in this test system. Cytogenetic studies: The capability of the three mycotoxins AFB1, AFG1, and PA to induce chromosome damages in vivo has been tested in the Chinese hamster by examination of bone marrow cells. The substances were tested in each of two oral doses (AFB1: 12, 5, and 25 mg/kg; 25 and 50 mg/kg; PA: 10 and 20 mg/kg). The present data show that the three mycotoxins induce chromosome aberrations in the following order of activity: PA greater than AFB1 greater than AFG1.

Studies on the embryotoxicity and mutagenicity of mycotoxins.

Embryotoxicity: Aflatoxin B1(AFB1), G1 (AFG1), and Patulin (PA) were investigated in NMRI mice for embryotoxic and teratogenic activity. These three mycotoxins were injected intraperitoneally or given orally on day 12 and 13 of pregnancy. AFB1 (15, 45, and 90 mg/kg ip or 45 mg/kg po) produced a moderate retardation in the fetal development and a dose related increase of cleft palates, wavy ribs, and diaphragm changes. The effects after injection of AFG1 (45 and 90 mg/kg ip) were reduction of fetal weights, increase of diaphragm changes, and malformations of kidneys. PA (1.25, 2.5, and 3.75 mg/kg ip or 3.75 mg/kg po) elevated the rate of cleft palates after 3.75mg/kg. In the dominant lethal assay neither PA (2.5 and 5 mg/kg ip) nor AFB1) (15 and 45 mg/kg ip) increased the frequency of the dominant lethal mutations. Both mycotoxins showed no mutagenic activity in this test system. The capability of AFB1, AFG1, and PA to induce chromosome damages in vivo was tested in the Chinese Hamster by examination of bone marrow cells, each after two oral doses (AFB1: 12.5 and 25 mg/kg; 25 and 50 mg/kg; PA: 10 and 20 mg/kg). The three mycotoxins induced chromosome aberrations in the following order of activity: PA > AFB1 > AFG1.

Induction of early lesions in the forestomach of rats by 3-tert-butyl-4-hydroxyanisole (BHA).

BHA was administered to Wistar rats at a dose level of 2% in a powdered diet for periods of 1, 2 and 4 wk. After 1 wk epithelial damage, mild hyperplasia and hyperkeratosis of the forestomach mucosa was observed. The hyperplasia and hyperkeratosis showed progression at wk 2 and 4 whereas other epithelial defects regressed. The lesions were most pronounced in the vicinity of the limiting ridge. A further 4 wk of feeding without BHA resulted in a complete regression of epithelial defects, although the hyperplastic changes were still apparent. Other rats were given 1 g BHA/kg body weight/day by gastric intubation in arachis oil for 1, 2, 4, 8, 16 or 32 days. Increased mitotic activity was observed after 1 day and mild hyperplasia after the second intubation, but inflammatory response and superficial defects were not prominent and the hyperplasia of the squamous epithelium did not appear to result from initial damage and subsequent hyper-regenerative activity. A gradual regression of the hyperplastic changes occurred after eight daily intubations. The lesions were found in the apex of the forestomach remote from the limiting ridge. It is concluded that BHA incorporated in powdered diet or given in arachis oil by oral intubation causes lesions in the rat forestomach similar to that reported for BHA given in a pelleted diet (Ito et al. J. natn. Cancer Inst. 1983, 70, 343; idem, Gann 1983, 74, 459). The hyperplastic changes in the mucosa occur rapidly and their localization is dependent on the mode of application. Following withdrawal of the BHA there was almost complete regression of the lesion, only a residual mild hyperplasia remaining after 4 wk.

[Comparative studies on the embryotoxicity of 2-methyl-4-chlorophenoxyacetic acid, mecoprop and dichlorprop in NMRI mice]. / Vergleichende Untersuchungen zur Embryotoxizität von 2-methyl-4-chlorphenoxyessigsäure, Mecoprop und Dichlorprop bei NMRI-Mäusen.

From the group of herbicidal phenoxy carbonic acids, 2-methyl-4-chlorophenoxyacetic acid (MCPA; 0-500 mg/kg), 2-(4-chloro-2-methyl-phenoxy) propionic acid (mecoprop/MCPP; 0-700 mg/kg) and 2-(2,4-dichlorophenoxy) propionic acid (dichlorprop/2,4-DP; 0-500 mg/kg) as well as the dextrorotatory compounds of MCPP (MCPPD; 0-500 mg/kg) and 2,4-DP (2,4-DPD; 0-500 mg/kg) were studied in NMRI mice after oral administration between days 6-15 of pregnancy. All five substances proved to be embryotoxic and teratogenic in varying intensity. MCPA proved to be most effective: it was embryotoxic from doses of 100 mg/kg and teratogenic from 200 mg/kg. The remaining compounds (MCPP, MCPPD, 2,4-DP, 2,4-DPD) were embryotoxic from doses of 300 mg/kg and caused malformations of the skeleton from 400 mg/kg. The embryocidal and teratogenic potencies of the dextrorotatory components of MCPA and 2,4-DP exceeded those of the corresponding racemates. Influences of MCPPD and 2,4-DPD upon postimplantative loses, frequency of cleft palates and wavy ribs appeared already at dosages being 100-200 mg/kg below those of the racemates given to the respective groups of experimental animals. Additional alterations of the skeleton were observed which did not occur following administration of the racemic mixtures: deformed centrums of thoracic vertebra and exencephaly.

[Studies on the embryotoxicity of monolinuron and buturon in NMRI-mice (author's transl)]. / Untersuchungen über die Embryotoxizität von Monolinuron und Buturon bei NMRI-Mäusen.

The acute LD50 in virginal NMRI-Mice was found to be 2528 mg/kg for monolinuron and 1791 mg/kg for buturon. Pregnant female mice of the NMRI strain were administered orally 25--1000 mg monolinuron/kg (I) and 100-400 mg buturon/kg (II) on days 6--15 of gestation and, during defined phases of fetal development (days 10--13 after conception), 500 mg I/kg and 350 mg II/kg. Following administration of 10 doses, an increase of postimplantative losses and clear retardation of development in the upper dose range from 100 mg I/kg and 300 mg II/kg as well as a dose-dependent increase of the rate of cleft palates could be observed. High doses of both substances given from day 6--15 of pregnancy produced minor numbers of wavy and fused ribs as well as hypoplasia of the upper jaw after application of monolinuron and exenteria and exencephaly after buturon. Administration of monolinuron between days 10 and 13 of gestation resulted a minor and that of buturon a clear increase of the number of cleft palates. To evaluate postnatal development 200 and 500 mg I/kg, and 200 and 300 mg II/kg were administered orally on days 6--15 of gestation. In the higher doses, both substances produced an increased mortality among the offspring up to 3 weeks after birth, and a clear increase of the rate of cleft palates.