Ronald D. Hood

Teratogenic Effects of Sodium Arsenate in Mice

Single intraperitoneal injections of sodium arsenate in Swiss-Webster mice on one of days 6 to 12 of gestation resulted in increased fetal resorptions. Decreased fetal weights and a spectrum of fetal anomalies were noted in litters treated on days 6 to 11. Malformations induced were day-dependent and included exencephaly, micrognathia, protruding tongue, agnathia, open eye, exophthalmos, anophthalmia, missing pinna, cleft lip, hydrocephalus, umbilical hernia, eventration, ectrodactyly, micromelia, and shortened or twisted tail and twisted limb, or both. Skeletal defects such as fused vertebrae and fused and forked ribs were also seen.

The Potential Adverse Health Effects of Dental Amalgam

There is significant public concern about the potential health effects of exposure to mercury vapour (Hg0) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg0, evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects.Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg0 is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg0 released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg0 and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg0 levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20–30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.

Effects of sodium arsenite on fetal development

SummarySingle intraperitoneal injections of sodium arsenite were given to albino Swiss-Webster mice on one of days 7–12 of gestation. Two dose levels were used: 10 or 12 mg/kg. Arsenite treatment resulted in high rates of fetal deaths and tended to decrease fetal weights-compared with H2O injected controls. Arsenite induced a variety of fetal malformations on gestation days 7–10; the most common were exencephaly, micrognathia, open eye, tail defects and skeletal anomalies of the ribs and vertebrae. Defects were similar to but less numerous than those caused by sodium arsenate.

Uptake, distribution, and metabolism of trivalent arsenic in the pregnant mouse

To investigate the distribution of trivalent arsenic (arsenite) in the pregnant rodent, CD-1 mice were dosed with sodium arsenite by ip injection or by gavage on gestation d 18 (copulation plug day = d 1). Doses were 8 (ip) or 25 (po) mg/kg, and samples of maternal blood, liver, and kidneys, as well as fetuses and pooled placentas, were analyzed for total arsenic at intervals of up to 24 h. Fetal tissue was also analyzed for relative proportions of inorganic arsenic and methylated metabolites. Arsenic uptake was significantly greater in the injected mice and their fetuses (as a proportion of the administered dose), with levels highest at 10 min to 4 h in maternal tissues and 24 h in fetuses. Peak maternal arsenic levels (as microgram/g or microgram/ml) ranged from 2.36 (blood) to 26.15 (liver) for the ip injected and 1.25 (blood) to 17.64 (liver) for the gavaged treatment group. The rate of arsenic elimination from maternal samples was not significantly influenced by administration route, with first-order elimination rate constants (k) of 0.215 and 0.234 h-1 for the po and ip dosed mice, respectively. Fetal tissue arsenic peaks were 2.10 and 0.77 micrograms/g for the ip and po treatment groups, respectively. The proportion of methylated arsenic in fetuses increased to 79% in the ip treatment group and 88% in the po group by 24 h. Such results show that much of the arsenic reaching the mouse fetus has been methylated to less toxic metabolites. They also confirm that assumptions made regarding hazard to the fetus must reflect the likelihood that a portion of any maternal dose of inorganic arsenite reaching a fetus may have been methylated, and they support previous findings that arsenite is toxic to the conceptus at lower doses when given by injection than by gavage.

Effects of rubratoxin B on prenatal development in mice.

SummarySingle doses (0.4, 0.6, 0.9, or 1.2 mg/kg) of rubratoxin B were given ip to albino mice on days 6–12 of gestation and fetuses were examined on day 18. Results indicated that rubratoxin is a growth retardant, a potent embryocide and a teratogen. Exencephaly, malformed pinnae, malformed jaws, umbilical hernia and open eye were the most commonly noted developmental anomalies associated with rubratoxin treatment.

ILSI/HESI maternal toxicity workshop summary : maternal toxicity and its impact on study design and data interpretation

Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36-51, 2010.

Effects of maternal restraint stress and sodium arsenate in mice.

Either maternal restraint stress or sodium arsenate treatment during pregnancy can cause adverse effects on the mouse conceptus. The current study assessed the effects of both factors administered concurrently. Five treatment groups were used initially: (1) vehicle (H2O) control [C], (2) feed/water deprived [FWD], (3) sodium arsenate [SA], (4) restraint only [R], and (5) sodium arsenate plus restraint [SA+R]. A sixth group, arsenate plus feed/water deprived [SA+FWD], was added later, along with (7) a concurrent arsenate-only control [SAC]. Mated female CD-1 mice in Groups 3, 5, 6, and 7 were injected ip with sodium arsenate (20 mg/kg) on gestation day (GD) 9 (plug = day 1). Group 5 mice were restrained for 12 h beginning immediately after dosing. Groups 4 and 5 were restrained in the supine position from 9:00 a.m. to 9:00 p.m. on GD 9; FWD mice were deprived during that time. All females were killed on GD 18 and subjected to teratologic examination. Significantly increased exencephaly and decreased fetal weight were seen in SA+R Group fetuses. The incidence of supernumerary ribs was significantly higher in the SA+R Group than in the SA Group but did not differ from the R Group. These results add to the evidence that maternal stress combined with a chemical teratogen may have a greater effect on the conceptus than would exposure to either agent alone.

Brain necrosis in mouse fetuses transplacentally exposed to the mycotoxin ochratoxin A

Ochratoxin A is a teratogenic and nephrotoxic mycotoxin produced by storage molds (chiefly species of Aspergillus and Penicillium) on a variety of cereal grains and other agricultural commodities. Pure crystalline ochratoxin A was dissolved in 0.1 n sodium bicarbonate solution and given to groups of 5 to 10 pregnant CD-1 mice at dose levels ranging from 3 to 5 mg/kg body weight. Dams were treated by gavage on the eighth, ninth, and tenth days of gestation or on the fifteenth, sixteenth, and seventeenth days of gestation. The dams were killed on the twentieth day of gestation and the fetal brains were fixed in formalin, processed, and examined by light microscopy. There was prominent and widespread cerebral necrosis in most fetuses from dams treated on Days 15 through 17. However, cerebral necrosis was not prominent in fetuses from dams treated on Days 8 through 10 when ochratoxin A is overtly teratogenic. These findings were also reproduced in ICR mice and in other groups of CD-1 mice treated with ochratoxin A that was dissolved in 0.1 n sodium bicarbonate and given by ip injection. Although single doses of ochratoxin A given on Day 8, 9, or 10 of gestation were teratogenic, single doses given on the fifteenth, sixteenth, or seventeenth day of gestation were insufficient to induce cerebral necrosis in the offspring.

Developmental toxicity assessment of the ionic liquid 1-butyl-3-methylimidazolium chloride in CD-1 mice

The effects of prenatal exposure of mice to the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([C4mim]Cl) were studied because of the potential for human exposure as a result of water or soil contamination from industrial effluent or accidental spills. After exposure to the IL, fetal weight was significantly decreased at the two highest dosages (P≤ 0.01). Malformations were also somewhat more numerous at the highest dosage, suggesting that [C4mim]Cl may be teratogenic, although the apparent increase was not statistically significant. Maternal toxicity was also present, as shown by a dose-dependent increase in maternal morbidity and mortality during the course of treatment. Therefore from these results, [C4mim]Cl appears to be developmentally toxic at maternally toxic dosages, although the mechanism is unknown.

Evaluation of the effect of BAL (2,3-dimercaptopropanol) on arsenite-induced teratogenesis in mice☆

The effect of the chelating agent dimercaprol (BAL) on the embryotoxic and teratogenic effects of arsenite (As3+) was determined. BAL (sc, 30 mg/kg) was administered to pregnant CD-1 mice, either 8 and 4 hr prior to or 4 and 8 hr after a 12-mg/kg ip dose of arsenite; other females received a single sc injection of 60 mg/kg BAL concurrently with the arsenite. Treatments were given on Gestation Day 9 or 12 (copulation plug = Day 1). Controls received sc corn oil or ip H2O, with or without arsenite or BAL. Arsenite treatment caused gross and skeletal malformations and prenatal deaths, while controls were unaffected. When BAL was given prior to arsenite on Day 9, incidences of prenatal mortality and skeletal malformation were significantly diminished, and on Day 12, BAL protected against fetocidal effects of arsenite when given concurrently with the arsenite. No other significant protective effects against arsenite toxicity were seen due to BAL; however, concurrent BAL treatment on Day 9 appeared to result in decreased fetal mortality and a decline in skeletal malformations. BAL given following arsenite on Day 9 afforded no significant protection against the arsenic, although an apparent decrease in gross and skeletal malformations was suggestive of such an effect. According to these results, BAL is unlikely to have a practical beneficial effect on the arsenite exposed conceptus, because it must be administered prior to the teratogen (or perhaps simultaneously with it) to be effective.