Jesper Bo Nielsen

Toxicologic evidence of developmental neurotoxicity of environmental chemicals

Developmental neurotoxicity constitutes effects occurring in the offspring primarily as a result of exposure of the mother during pregnancy and lactation. To exert their effect, these chemicals or their metabolites must pass the placenta and/or the blood-brain barrier. In experimental animals, exposure to neurotoxic chemicals during critical periods of brain development has induced permanent functional disturbances in the CNS. Although available data suggest that proper animal models exist, only few chemicals have been tested. Neurotoxicity testing is not required by national authorities for classification of chemicals. Epidemiological evidence is very limited, but severe irreversible effects have been observed in humans following in utero exposures to a few known developmental neurotoxicants. The large number of chemicals with a potential for developmental neurotoxicity in humans stresses the importance of generating basic kinetic data on these chemicals based on relevant experimental models. First of all, data are needed on their ability to pass the placenta and the developing blood-brain barrier, to accumulate, and to be metabolized in the placenta and/or the fetus. These kinetic data will be essential in establishing a scientifically based hazard evaluation and risk assessment.

Toxicokinetics of mercuric chloride and methylmercuric chloride in mice

Future human exposure to inorganic mercury will probably lead to a few individuals occupationally exposed to high levels and much larger populations exposed to low or very low levels from dental fillings or from food items containing inorganic mercury; human exposure to methylmercury will be relatively low and depending on intake of marine food. Ideally, risk assessment is based on detailed knowledge of relations between external and internal dose, organ levels, and their relation to toxic symptoms. However, human data on these toxicokinetic parameters originate mainly from individuals or smaller populations accidentally exposed for shorter periods to relatively high mercury levels, but with unknown total body burden. Thus, assessment of risk associated with exposure to low levels of mercury will largely depend on data from animal experiments. Previous investigations of the toxicokinetics of mercuric compounds almost exclusively employed parenteral administration of relatively high doses of soluble mercuric salts. However, human exposure is primarily pulmonary or oral and at low doses. The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice. Major findings using this model are discussed in relation to previous knowledge. The toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex, whereas the mouse strain used is less important. The true absorption of a single oral dose of HgCl2 was calculated to be about 20% at two different dose levels. Earlier studies that did not take into account the possible excretion of absorbed mercury and intestinal reabsorption during the experimental period report 7-10% intestinal uptake. The higher excretion rates observed after oral than after intraperitoneal administration of HgCl2 are most likely due to differences in disposition of systemically delivered and retained mercury. After methylmercury administration, mercury excretion followed first-order kinetics for 2 wk, independently of administration route, strain, or sex. However, during longer experimental periods, the increasing relative carcass retention (slower rate of excretion) caused the elimination to deviate from first-order kinetics. Extensive differences in the toxicokinetics of methylmercury with respect to excretion rates, organ deposition, and blood levels were observed between males and females.(ABSTRACT TRUNCATED AT 400 WORDS)

Disposition and retention of mercuric chloride in mice after oral and parenteral administration

The present study compares effects of dose size on whole-body retention and relative organ distribution of 203HgCl2, after oral and intraperitoneal administration to female mice of two strains (inbred CBA/Bom and outbred Bom:NMRI). Using whole-body retention data of oral and intraperitoneal administration, an estimated true absorption of a single oral dose of inorganic mercury was calculated to be about 20% at two different dose levels. At the highest oral dose, a delay in fecal elimination of nonabsorbed mercury was observed, indicating a decreased peristaltic rate. The relative hepatic deposition was larger after oral than after intraperitoneal administration, presumably due to a first-pass effect, and a correspondingly lower relative renal deposition was seen. Increasing doses at both exposure routes resulted in increasing relative deposition in liver, stomach, intestines, and spleen but decreasing relative deposition in lungs and kidneys. Bom:NMRI mice deposited a larger fraction of the whole-body burden in the kidneys and a smaller fraction in the livers than did CBA/Bom mice. Comparison to a previous study with male mice (Nielsen and Andersen, 1989) demonstrates that male and female mice deposit similar fractions of their body burden in the liver, while male mice deposit significantly larger amounts of mercury in the kidneys and smaller amounts in the carcass than do female mice. Thus, the toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex; the mouse strain is of less importance than the other factors investigated. The absorption of inorganic mercury was estimated to be about 20%, that is, twice as high as earlier estimates.

Oral mercuric chloride exposure in mice: effects of dose on intestinal absorption and relative organ distribution

Human intoxications with inorganic mercury occur via the oral or pulmonar routes. However, earlier experimental studies of the acute toxicity of inorganic mercury primarily used parenteral administration of soluble inorganic mercury salts. The present study evaluated the effect of dose size on intestinal absorption and relative organ distribution of orally administered mercuric chloride. Experiments were performed with male mice of 2 strains (inbred CBA/Bom and outbred Bom: NMRI). At the highest dose of HgCl2, a delay in fecal elimination of non-absorbed mercury was observed indicating a decreased peristaltic rate. The fractional whole-body retention of mercury at 14 days after dosage was inversely related to the dose size, conceivably due either to saturation of the uptake mechanism or to damage to the kidneys resulting in loss of mercury with the urine at the highest dose levels. The relative organ distribution of mercury after oral exposure was quantitatively different from that reported in the literature after parenteral administration of inorganic mercury. Thus, the relative hepatic deposition was larger than after injection of mercury, presumably due to the first pass effect. A dose dependency in the relative organ distribution of retained mercury was observed, characterized by increasing relative deposition in liver, stomach, intestines, testes, spleen and carcass but decreasing relative renal deposition with increasing dose. The toxicokinetics of inorganic mercury was similar in the 2 mice strains. The present study demonstrates that the toxicokinetics of orally administered inorganic mercury is different from that of parenterally administered inorganic mercury as earlier reported in the literature.

Toxic metals and selenium in blood from pilot whales (Globicephala melas) and sperm whales (Physeter catodon)

Abstract Mercury, lead, cadmium and selenium were measured in blood from pilot whales ( Globicephala melas ) caught at the Faroe Islands and in blood from four sperm whales ( Physeter catodon ) stranded in Denmark. The median whole-blood concentration of mercury in pilot whales was 229 μg/l with a positive correlation to the corresponding selenium concentrations. Blood concentrations of mercury and cadmium up to 2421 and 31xa0100 μg/l, respectively, were found in the sperm whales. Cadmium concentration averaged 500–1000 times higher in stranded sperm whales than in the pilot whales. The mercury and cadmium concentrations dramatically exceed levels which are associated with severe toxicity in several other mammal species.

Oral cadmium chloride intoxication in mice: Effects of chelation

In acute oral cadmium intoxication, the immediate target organ is the gastrointestinal tract. In this study, toxic effects following oral administration of CdCl2 to mice by stomach tube included intestinal paralysis, constipation and necrosis of the gastrointestinal epithelia. Tissue damage in liver, kidneys and testes developed in survivors due to the systemic toxicity of absorbed cadmium. Chelation of the Cd2+ ion by STPP, EDTA or DTPA prior to oral administration reduced mortality, tissue damage and whole body retention of cadmium. Other chelators (cysteine, NTA, DDC) only marginally affected the whole-body retention. DDC even enhanced the inhibition of intestinal motility caused by cadmium. DTPA and DDC decreased the relative deposition in the liver and increased the relative renal deposition. DDC also increased the relative cadmium deposition in brain, lung, spleen and testes. Among the chelators tested, DTPA was most efficient in preventing toxic effects of oral cadmium.

Oral cadmium chloride intoxication in mice: diethyldithiocarbamate enhances rather than alleviates acute toxicity.

Diethyldithiocarbamate (DDC) is known to alleviate acute toxicity due to injection of cadmium salts. However, when cadmium chloride was administered by the oral route, DDC enhanced rather than alleviated the acute toxicity; both oral and intraperitoneal (i.p.) administration of DDC had this effect. Thus, orally administered DDC enhanced cadmium-induced duodenal and ileal tissue damage and inhibition of peristalsis, as indicated by an increased intestinal transit time. At low cadmium doses, the whole-body retention of cadmium was increased by oral DDC administration. Intraperitoneally administered DDC increased cadmium-induced acute mortality and testicular necrosis, and it enhanced cadmium-induced reduction of intestinal motility and increased the whole-body retention of cadmium, indicating increased intestinal cadmium absorption. Also, DDC changed the organ distribution of absorbed cadmium: after i.p. administration of DDC, the relative hepatic deposition was reduced, whereas the relative deposition in other organs, in particular the brain, was increased. This study indicates that medical use of DDC should be avoided in individuals with current exposure to cadmium.

Evaluation of mercury in hair, blood and muscle as biomarkers for methylmercury exposure in male and female mice

Recently established reference intervals demonstrate that blood mercury is significantly higher in women than in men. Mercury in blood and hair are both used as biomarkers for human methylmercury exposure and employed in risk assessment without considering possible sex-related differences in toxicokinetics of methylmercury. In an experimental study using male and female mice of three different strains, the validty of mercury in hair, blood and muscle as indicators of methylmercury exposure was evaluated. Significant sex-related differences in the toxicokinetics of methylmercury were observed in the mice and it is concluded that hair and blood levels of mercury are of questionable relevance as indicators of both body burden and target organ concentrations of mercury. However, blood concentrations might be used as an indicator of brain deposition and the correlation improves after corrections due to sex-related differences in toxicokinetics.

The toxicokinetics of mercury in mice offspring after maternal exposure to methylmercury — effect of selenomethionine

Human evidence indicates fetotoxicity of methylmercury at exposure levels inducing only slight and reversible maternal toxicity, but experimental animal data demonstrate, that fetotoxicity may occur despite absence of noticeable maternal toxicity. However, in contrast to the long-term exposure in humans, the key point in the experimental design of the majority of experimental studies has been administration of few doses of methylmercury late in gestation. The present study in mice therefore used long-term maternal exposure to methylmercury (1 nmol/ml in drinking water) and a cross-fostering design to investigate separately in different offsprings the toxicokinetics of transplacentally absorbed mercury and mercury retained during lactation. Further, the influence of seleno-L-methionine (3 micrograms/ml in drinking water) on the toxicokinetics of methylmercury in these mice was studied. The present study demonstrated, that independent on seleno-L-methionine supplementation, offspring deposited equal amounts of mercury during lactation and during gestation. Moreover, the organ distribution and rate of excretion of mercury in transplacentally exposed mice were considerably different from those in mice exposed postnatally and from adult mice in studies using comparable dosages. Seleno-L-methionine only slightly affected the toxicokinetics of mercury in offspring.

Mercuric chloride-induced kidney damage in mice: time course and effect of dose.

The rate of elimination of mercury after a single oral or intraperitoneal administration of HgCl2 to male or female mice has recently been demonstrated to be inversely related to the dose size (Nielsen and Andersen, 1989, 1990). The present study demonstrates dose-related induction of renal tubular damage, followed by regeneration, after oral administration of HgCl2 to female mice. Dose-related increased fractional urinary mercury excretion (expressed as percent of dose) was also demonstrated. At increasing dose of HgCl2, the renal activity of selenium-dependent glutathione peroxidase decreased, and was only 50% of the activity in untreated controls after administration of 200 mumol HgCl2/kg. At higher doses, the renal concentration of glutathione was significantly reduced as well. The degree of tissue damage was inversely related to the fractional deposition of mercury in the kidneys. This study indicates that the reduction in fractional whole-body retention of mercury with increasing dose size previously demonstrated is due to increased urinary mercury excretion during transient renal damage followed by regeneration, as extensive leakage took place before extensive regeneration was noted.