Placental and lactational transfer of ochratoxin A in rats.

The placental and lactational transfer of ochratoxin A (OA) was investigated in a cross-fostering study in rats. Dams were given 50 microg OA(-1) kg body weight by gastric intubations 5 times a week for 2 weeks before mating, during gestation and then 7 days a week during lactation. Neonates from OA-treated dams were cross-fostered at birth to control dams treated with only vehicle. In the same way, neonates from control dams were cross-fostered to OA-treated dams. Treatment with OA did not result in any effects on birth weight or growth development of the pups during the first 21 days of life. There were no effects on milk quality as measured by milk lipids, protein or lactose concentrations, or on milk production, assessed by the mammary gland content of RNA and DNA. A mean milk:blood ratio of approximately 0.6 was found. The dose of OA from milk to the suckling pup at 14 days of age can be calculated to about 50 microg kg(-1) body weight(-1) day, which is similar to the dose given to the dams. Pups exposed to OA only via milk had blood and kidney levels of OA approximately 3 times higher than their dams, indicating a high absorption and/or a low excretion of OA in the sucklings. At 14 days of age the highest blood and kidney levels of OA were found in offspring exposed both via placenta and milk, with the highest contribution from milk. Offspring exposed only via milk had about 4-5 times higher levels of OA in blood and kidney compared to offspring exposed only via placenta. As milk could be a significant source of OA exposure in newborns, adverse health effects resulting from postnatal exposure should be studied and evaluated in the risk assessment of OA.

Kinetics of methylmercury and inorganic mercury in lactating and nonlactating mice.

The elimination of mercury was followed for 9 days (Days 10-19 of lactation) in milk and/or 21 days in blood and plasma of lactating and nonlactating mice administered a single iv injection of either 203Hg-labeled methylmercuric chloride or 203Hg-labeled mercuric chloride (0.5 mg Hg/kg body wt). Demethylation of methylmercury to inorganic mercury was taken into consideration by analyzing the data with a combined pharmacokinetic model based on the assumption of constant blood plasma ratios for methylmercury and inorganic mercury. A three-compartment model fitted the blood and plasma concentrations vs time profiles for both compounds. Plasma clearance and volume of distribution at steady state for methylmercury were 95. 3 ml/h/kg and 18,500 ml/kg, respectively, in lactating mice, and significantly higher than in nonlactating mice with values of 47.1 ml/h/kg and 9400 ml/kg, respectively. The terminal half-lives of methylmercury in plasma were similar, 170 h in lactating and 158 h in nonlactating mice. No differences were observed between the pharmacokinetic parameters in lactating and nonlactating mice administered inorganic mercury. The lactational transfer of mercury was more efficient following administration of inorganic mercury than after administration of methylmercury, with a five times higher peak concentration in milk, higher milk:plasma concentration ratios, and 8% of the administered dose excreted in milk compared with 4% for methylmercury. Mercury concentrations in milk following an iv dose of inorganic mercury decreased with a terminal half-life of 107 h, whereas after administration of methylmercury, the concentration of total mercury in milk remained at an almost constant level during the whole period of investigation. There was a nonlinear relationship between mercury in milk and plasma following inorganic mercury administration. It is suggested that inorganic mercury enters the mammary gland by a carrier-mediated transport system, which is saturated at high plasma levels of inorganic mercury. The present study shows that physiological changes during lactation alter the pharmacokinetics for methylmercury in mice but not for inorganic mercury.

Total and inorganic mercury in breast milk in relation to fish consumption and amalgam in lactating women.

Total mercury concentrations (mean +/- standard deviation) in breast milk, blood, and hair samples collected 6 wk after delivery from 30 women who lived in the north of Sweden were 0.6 +/- 0.4 ng/g (3.0 +/- 2.0 nmol/kg), 2.3 +/- 1.0 ng/g (11.5 +/- 5.0 nmol/kg), and 0.28 +/- 0.16 microg/g (1.40 +/- 0.80 micromol/kg), respectively. In milk, an average of 51% of total mercury was in the form of inorganic mercury, whereas in blood an average of only 26% was present in the inorganic form. Total and inorganic mercury levels in blood (r = .55, p = .003; and r = .46, p = .01 6; respectively) and milk (r = .47, p = .01; and r = .45, p = .018; respectively) were correlated with the number of amalgam fillings. The concentrations of total mercury and organic mercury (calculated by subtraction of inorganic mercury from total mercury) in blood (r = .59, p = .0006, and r = .56, p = .001; respectively) and total mercury in hair (r = .52, p = .006) were correlated with the estimated recent exposure to methylmercury via intake of fish. There was no significant between the milk levels of mercury in any chemical form and the estimated methylmercury intake. A significant correlation was found between levels of total mercury in blood and in milk (r = .66, p = .0001), with milk levels being an average of 27% of the blood levels. There was an association between inorganic mercury in blood and milk (r = .96, p < .0001); the average level of inorganic mercury in milk was 55% of the level of inorganic mercury in blood. No significant correlations were found between the levels of any form of mercury in milk and the levels of organic mercury in blood. The results indicated that there was an efficient transfer of inorganic mercury from blood to milk and that, in this population, mercury from amalgam fillings was the main source of mercury in milk. Exposure of the infant to mercury from breast milk was calculated to range up to 0.3 microg/kg x d, of which approximately one-half was inorganic mercury. This exposure, however, corresponds to approximately one-half the tolerable daily intake for adults recommended by the World Health Organization. We concluded that efforts should be made to decrease mercury burden in fertile women.

Toxicokinetics of lead in lactating and nonlactating mice.

Toxicokinetics of lead in lactating and nonlactating mice were studied after a single intravenous injection of 0.05 mg of lead (2.5 mCi 203Pb)/kg. Lead concentrations in blood, plasma, and milk were measured for 10 days following dosing. The volume of distribution based on plasma lead was more than two times larger in lactating than in nonlactating mice, 133 and 58 liter/kg, respectively. Plasma lead clearance in lactating mice was 4.25 liter/hr/kg compared with 1.07 liter/hr/kg in nonlactating mice. However, no such pronounced difference in blood lead clearance was found between the two groups, indicating that this parameter does not reveal the kinetic characteristics during lactation. Milk was found to be an additional route of excretion for lead. About 1/3 of the administered dose of lead was excreted in milk. Accordingly, milk clearance contributed to 1/3 of the total plasma clearance in the mice. The relationships of lead in plasma to lead in whole blood as well as lead in milk to lead in whole blood were nonlinear, with a relatively higher increase in plasma and in milk lead levels at higher blood lead levels. This nonlinearity may be explained by a reduced uptake of lead in erythrocytes as the lead binding sites of these cells become saturated. In lactating mice, the maximum binding capacity of lead in red blood cells was even lower than in nonlactating mice. Similar nonlinear relationship have have also been found in human studies although at much higher levels of lead in blood. The milk:plasma concentration ratio for lead was found to be between 50 and 100 after 24 hr, demonstrating a much more efficient excretion of lead into milk than what is known from human studies. Differences in the milk composition may be one explanation for the species differences in milk excretion of lead. The present study shows that physiological changes during lactation alter the pharmacokinetics of lead in mice.

Distribution of lead in lactating mice and suckling offspring with special emphasis on the mammary gland.

The distribution of lead in lactating mice and suckling offspring was studied with whole body autoradiography at 4 and 24 h after a single intravenous injection of 203Pb (50 nmol Pb/kg) to the dams. In the lactating mice on day 14 of lactation, the highest uptake of radioactivity at 4 h after administration was recorded in renal cortex, skeleton and liver. A high uptake was also evident in the mammary gland. At 24 h after administration, the radioactivity had decreased in most organs except in the skeleton. In the suckling pups, exposed to lead only via dams' milk for 24 h, the highest level of radioactivity was present in the intestinal mucosa and a much lower level of radioactivity was present in the skeleton. The mammary glands from mice given three daily intravenous injections of 240 mumol Pb/kg were examined with X-ray microanalysis. At 4 h after the last injection, lead was found associated with casein micelles both inside the alveolar cell and in the milk lumen, indicating that lead is excreted into the milk, bound to casein, via the Golgi secretory system.

Effects of ochratoxin A on the rat immune system after perinatal exposure.

Effects on the immune system after perinatal exposure to ochratoxin A (OA) were studied in Sprague-Dawley rats after single or repeated exposure of the dams. In a short-term study, dams with litters were given a single dose of OA (0, 10, 50 or 250 micrograms/kg body weight) on day 11 of lactation. The effects on cell numbers in spleen and thymus añd on the mitogen responses of lymphocytes were evaluated in the suckling pups on day 14 of lactation. The proliferative response of splenocytes to the T-cell mitogen Concanavalin A (Con A) was significantly stimulated in pups from dams given 10 or 50 micrograms OA/kg body weight as compared to control pups. In addition, proliferation of thymocytes in response to Con A was stimulated in pups from dams exposed to 50 micrograms OA/kg body weight. In a long-term, cross-fostering study comparing pre- and postnatal exposure, half of the dams received 50 micrograms OA/kg body weight 5 days a week by gastric intubation 2 weeks before mating, during gestation and then 7 days a week until weaning. Effects on immune parameters were studied in the pups on day 14 of lactation and at 13 weeks of age. Suppressed mitogenic responses were seen to both lipopolysaccharide (LPS) and Con A in prenatally exposed pups sampled on day 14 of lactation. At 13 weeks the response of splenocytes to LPS was still impaired. The primary antibody response to a viral antigen was also lower in the prenatally exposed pups than in the control pups. These effects on the immune response were not seen in the groups of pups exposed postnatally or both pre- and postnatally, although blood concentrations of OA were higher in these groups at the time of the first sampling. This indicates that the decrease in proliferation and antibody production resulted from prenatal modulation of the immune system. The results show that prenatal exposure to relatively low doses of OA may induce immunosuppression. In contrast, short-term exposure of suckling pups to OA via the milk stimulates the proliferative responses of lymphocytes to polyclonal activation.

Bioavailability of lead from various milk diets studied in a suckling rat model.

The bioavailability of lead from various milk diets was studied in 14 day old suckling rats. Human milk, infant formula, cow's milk, rat milk and deionized water labeled with 203Pb were given to rat pups by gastric intubation. Animals were killed after 2 or 6 h and the radioactivity in the tissues was measured. At 2 h after administration the lead bioavailability, defined as lead uptake in the body, excluding the gastrointestinal tract, was 47% from water, 42% from human milk, 40% from infant formula, 31% from cow's milk and 11% from rat milk. After 6 h the bioavailability of lead was about 50% from water and human milk, 45% from infant formula and cow's milk, and 36% from rat milk. The blood lead levels in the pups reflected the total body uptake and were also correlated to the brain lead levels. Thus, rat pups given lead in human milk had approximately twice as high lead levels in blood and brain than pups given lead in rat milk. The intestinal absorption of lead was dependent on the milk diet given to the sucklings. In duodenum, the highest uptake of lead was found in rats given water or human milk, whereas in rats given rat or cow's milk the highest uptake of lead was found in ileum. The distribution of lead in cream, whey and casein fractions of the milk diets after in vitro labeling with 203Pb was also studied. The casein fraction in cow's and rat milk contained 90-96% of the total amount of lead in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Lead and cadmium levels in human milk and blood.

Lead and cadmium levels were determined (with AAS) in blood and milk obtained at 6 weeks after delivery from women living in the vicinity of a copper and lead metal smelter and in a control area. Analysis of lead and cadmium were also performed in blood samples obtained at delivery. Accuracy of the analysis was confirmed by the analysis of quality control samples. In general, blood and milk levels of lead and cadmium were low in both areas. At 6 weeks after delivery the lead levels in blood and milk were 32 +/- 8 and 0.7 +/- 0.4 micrograms Pb/l, respectively (total mean +/- S.D., n = 75). Cadmium levels in blood and milk were 0.9 +/- 0.3 and 0.06 +/- 0.04 microgram Cd/l, respectively (n = 75). At delivery the lead levels in blood of women in the smelter area were higher, 38.7 micrograms Pb/l, than the blood lead levels in women from the control area, 32.3 micrograms Pb/l, (P < 0.001). At 6 weeks after delivery there was no difference in blood lead levels between the two groups. In contrast, the lead levels in milk were higher in women from the smelter area, 0.9 microgram Pb/l, than in women from the control area, 0.5 microgram Pb/l, (P < 0.001). No differences in blood cadmium levels were found between the two groups. Milk cadmium levels in women from the control area, 0.07 microgram Cd/l, were somewhat higher (P < 0.01) than in women from the smelter area, 0.05 microgram Cd/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Placental and lactational transfer of lead in rats: a study on the lactational process and effects on offspring.

The effects of placental and lactational exposure to lead (Pb) were studied in suckling rats after long-term exposure of their dams to Pb in drinking water. Dams were given 12 mM Pb-acetate in the drinking water 8 weeks prior to mating and during gestation. One group of dams was also continuously exposed during lactation until day 15. Neonates from Pb-treated dams were cross-fostered at birth to control dams treated with Na-acetate (12 mM) in the drinking water. In the same way, neonates from dams receiving control water were in the same way cross-fostered to Pb-exposed dams. All animals were killed at day 15 of lactation, when measurements were performed. Continuous Pb exposure during gestation and lactation resulted in milk Pb levels approximately 2.5 times higher than the blood Pb levels. When Pb exposure was terminated at parturition the milk Pb levels were at a level similar to those of blood Pb at day 15 of lactation, and only 10% of the milk levels found after continuous Pb exposure. Exposure to Pb via placenta and milk in offspring from dams exposed continuously resulted in more than 6 times higher blood and brain Pb levels than in offspring exposed only via the placenta. Exposure only via milk in offspring from dams exposed to Pb until parturition resulted in higher blood Pb levels than in offspring exposed to Pb only via the placenta. This indicates that the lactational transfer after current or recent exposure of Pb in dams is considerably higher than placental transfer. Offspring in all the exposed groups had decreased ALAD activity in the blood. An exponential relationship between blood Pb levels and ALAD activity was demonstrated in the offspring. Due to the exponential decrease in ALAD activity at increasing blood Pb levels, ALAD is particularly sensitive in reflecting differences in Pb exposure within the lowest range of blood Pb levels. There was a slight effect on weight gain in the offspring. However, there was no effect on milk quality, as measure by milk lipid, protein and calcium concentrations, nor on milk production assessed by the mammary gland RNA and DNA content. This indicates that the effect on weight gain was a direct effect of Pb in the offspring.

Dose dependent transfer of 203lead to milk and tissue uptake in suckling offspring studied in rats and mice.

The dose-dependent transfer of 203Pb to milk and uptake in suckling rats and mice during a three-day nursing period was studied. On day 14 of lactation, the dams were administered a single intravenous dose of lead, labelled with 203Pb, in four or five doses from 0.0005 to 2.0 mg Pb/kg b.wt. There was a linear relationship between Pb levels in plasma and milk of both species. The Pb milk:plasma ratios at 24 hr after administration were 119 and 89 in mice and rats, respectively. At 72 hr the Pb milk:plasma ratio had decreased to 72 in mice and 35 in rats. The tissue levels of lead in the suckling rats and mice were also linearly correlated with lead concentration in milk at 72 hr, showing that milk could be used as an indicator of lead exposure to the suckling offspring. It is concluded that lead is transported into rat and mouse milk to a very high extent and the excretion into milk is more efficient in mice than in rats. On the other hand, rat pups had higher lead levels in tissues than mice pups, which might be due to a higher bioavailability and/or a lower excretion of lead in rat pups. Thus, lead in breast milk could be used as a biological indicator of lead exposure in the mother as well as in the suckling offspring.