Potential estrogenic and antiestrogenic activity of the cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) in immature rats using the uterotrophic assay.

The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) have numerous industrial and consumer applications and thus have the potential for human exposure. The present study was undertaken to examine potential estrogenic and antiestrogenic activities of D4 and HMDS. To address potential differences in sensitivity between rat strains the study used both Sprague-Dawley (SD) and Fischer 344 (F-344) rats. Estrogenicity of the test compounds was determined by measuring absolute and relative uterine weights in immature rats and by monitoring uterine epithelial cell height. In order to place the data obtained for D4 into perspective relative to strong and weak estrogenic compounds, the response produced by D4 at 0, 10, 50, 100, 250, 500, and 1000 mg/kg/day was compared to responses produced by ethinyl estradiol (EE) (1, 3, 10, or 30 microg/kg/day), diethylstilbestrol dipropionate (DES-DP) (0.5, 1.5, 5, 15 microg/kg/day), and coumestrol (CE) (10, 35, 75, 150 mg/kg/day). Antiestrogenic effects were evaluated by co-administering D4 (500 mg/kg/day) with EE at 1, 3, 10, and 30 microg /kg/day. All compounds were administered in sesame oil at a volume of 5 mL/kg by oral gavage. Beginning on postnatal day 18 (SD) or 21 (F-344) each pup (12 per group) received a single dose of test compound once a day for 4 consecutive days. The pups were euthanized the morning after the last treatment and their uteri removed, weighed, and processed for histological examination. EE and DES-DP produced a significant dose-dependent increase in absolute and relative uterine weights and uterine cell height. The maximum increase in uterine weight following EE exposure was approximately 350% relative to controls in both strains. The weak phytoestrogen CE also produced a dose-related increase in absolute and relative uterine weight and epithelial cell height, but the response occurred over a much higher range of doses. At the highest dose of CE, uterine weight was increased approximately 230% relative to controls. Following exposure to D4, absolute and relative uterine weights and uterine epithelial cell height were statistically significantly increased in both strains of rats at doses above 100 mg/kg/day. In terms of uterine weight, D4 was approximately 0.6 million times less potent than EE or DES-DP in SD pups and 3.8 million times less potent than EE or DES-DP in F-344 pups. The maximal increase in uterine weight, relative to controls, produced by D4 at 1000 mg/kg/day was approximately 160% in SD rats, while the maximum increase produced by D4 in F-344 rats was 86%. D4 co-administered over a wide range of EE doses, resulted in a significant reduction in uterine weight compared to EE alone. HMDS was evaluated in SD rats only. The response produced by HMDS (600 and 1200 mg/kg/day) was compared to EE (3 microg/kg/day). Antiestrogenic effects were evaluated by co-administering HMDS (1200 mg/kg/day) with EE at 3 microg/kg/day. HMDS had no measurable effect on uterine weight under the experimental conditions described here. However, HMDS coadministered with EE did produce a small, but statistically significant reduction in uterine weight compared to EE alone. In conclusion, D4 showed weak estrogenic and antiestrogenic activity that was several orders of magnitude less potent than EE, and many times less potent than the weak phytoestrogen CE.

Repeated inhalation exposure to octamethylcyclotetrasiloxane produces hepatomegaly, transient hepatic hyperplasia, and sustained hypertrophy in female Fischer 344 rats in a manner similar to phenobarbital.

Octamethylcyclotetrasiloxane (D4) has been described as a phenobarbital-like inducer of hepatic enzymes. Phenobarbital (PB) and phenobarbital-like chemicals induce transient hepatic and thyroid hyperplasia and sustained hypertrophy in rats and mice. The extent to which these processes are involved with D4-induced hepatomegaly is not known. The present study has evaluated the effects of repeated inhalation exposure to D4 vapors on hepatic and thyroid cell proliferation and hypertrophy with respect to time and exposure concentration. Female Fischer 344 rats were exposed via whole body inhalation to 0 ppm D4, 700 ppm D4 vapors (6 h/day; 5 days/week), or 0.05% PB in drinking water over a 4-week period. Incorporation of 5'-bromo-2-deoxyuridine (BrdU) and the abundance of proliferating cell nuclear antigen were used as indicators of cell proliferation. Designated animals from each treatment group were euthanized on study days 6, 13, and 27. The effect of D4 exposure concentration on hepatic cell proliferation was evaluated at 0, 7, 30, 70, 150, 300, or 700 ppm. Liver-to-body weight ratios in animals exposed to 700 ppm D4 were increased 18, 20, and 22% over controls while PB-treated animals showed increases of 33, 27, and 27% over controls on days 6, 13, and 27 respectively. Hepatic incorporation of BrdU following exposure to D4 was highest on day 6 (labeling index = 15-22%) and was at or below control values by day 27. This pattern of transient hyperplasia was observed in all hepatic lobes examined and was similar to the pattern observed following treatment with PB.

Hexamethyidisiloxane: A 13-week subchronic whole-body vapor inhalation toxicity study in Fischer 344 rats.

Hexamethyldisiloxane (HMDS) is a volatile linear siloxane dimer used in many applications, including precision cleaning, active ingredient carrier, and as a manufacturing intermediate. The purpose of this study was to characterize the subchronic vapor inhalation toxicity of the material as part of a comprehensive toxicology program. Groups of 20 male and 20 female Fischer 344 (F344) rats were exposed to nominal (and mean actual) vapor concentrations of 0, 50 (50), 200 (194), 600 (593), 1,500 (1,509) and 5,000 (5,012) ppm of HMDS, 6 hours per day, 5 days per week, for 13 weeks. No treatment-related signs of clinical toxicity or mortality, statistically significant effects upon body weight gain or food consumption, ophthalmoscopic changes, gross macroscopic necropsy findings, or organ weight changes were noted. Minor hematological, clinical biochemical, and urinalysis changes were seen but were not considered to be of toxicological relevance. Histological lesions in the kidney apparently consistent with male rat-specific alpha-2-urinary globulin nephropathy were observed in male rats exposed to 593, 1,509, and 5,012 ppm of HMDS, accompanied by slightly increased plasma urea and creatinine concentrations. No other treatment-related histological changes were seen in HMDS-exposed rats.

Disposition of radioactivity in fischer 344 rats after single and multiple inhalation exposure to [(14)C]Octamethylcyclotetrasiloxane ([(14)C]D(4)).

The retention, distribution, metabolism, and excretion of [(14)C]octamethylcyclotetrasiloxane (D(4)) were studied in Fischer 344 rats after single and multiple exposures to 7, 70, or 700 ppm [(14)C]D(4). Subset groups were established for body burden, distribution, and elimination. Retention of inhaled D(4) was relatively low (5-6% of inhaled D(4)). Radioactivity derived from [(14)C]D(4) inhalation was widely distributed to tissues of the rat. Maximum concentrations of radioactivity in plasma and tissues (except fat) occurred at the end of exposure and up to 3 h postexposure. Maximum concentrations of radioactivity in fat occurred as late as 24 h postexposure. Fat was a depot, elimination of radioactivity from this tissue was much slower than from plasma and other tissues. With minor exceptions, there were no consistent gender effects on the distribution of radioactivity and the concentrations of radioactivity were nearly proportional to exposure concentration over the exposure range. Excretion of radioactivity was via exhaled breath and urine, and, to a much lesser extent, feces. Urinary metabolites included dimethylsilanediol and methylsilanetriol plus five minor metabolites. Relative abundance of these metabolites was the same from every test group. Elimination was rapid during the first 24 h after exposure and was slower thereafter (measured up to 168 h postexposure). In singly-exposed female (but not male) rats, small dose-dependent shifts in elimination pathways were seen. After multiple exposures, the elimination pathways were dose- and gender-independent. These data define possible pathways for metabolism of D(4) and allow estimation of the persistence of D(4) and/or its metabolites in rats.

Induction of hepatic xenobiotic metabolizing enzymes in female Fischer-344 rats following repeated inhalation exposure to decamethylcyclopentasiloxane (D5).

Decamethylcyclopentasiloxane (D5) is a cyclic siloxane with a wide range of commercial applications. The present study was designed to investigate the effects of D5 on the expression and activity of selected rat hepatic phase I and phase II metabolizing enzymes. Female Fischer-344 rats were exposed to 160 ppm D5 vapors (6 h/day, 7 days/week, for 28 days) by whole-body inhalation. Changes in the activity and relative abundance of hepatic microsomal cytochromes P450 (CYP1A, CYP2B, CYP3A, and CYP4A), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were measured. Repeated inhalation exposure of rats to D5 increased liver size by 16% relative to controls by day 28. During a 14-day post-exposure period, liver size in D5-exposed animals showed significant recovery. Exposure to D5 did not change total hepatic P450, but increased the activity of hepatic NADPH-cytochrome c reductase by 1.4-fold. An evaluation of cytochrome P450 (CYP) enzymes in hepatic microsomes prepared from D5-exposed rats revealed a slight (1.8-fold) increase in 7-ethoxyresorufin O-deethylase (EROD) activity, but no change in immunoreactive CYP1A1/2 protein. A moderate increase (4.2-fold) in both 7-pentoxyresorufin O-depentylase (PROD) activity and immunoreactive CYP2B1/2 protein (3.3-fold) was observed. Testosterone 6beta-hydroxylase activity was also increased (2.4-fold) as was CYP3A1/2 immunoreactive protein. Although a small increase in 11- and 12-hydroxylation of lauric acid was detected, no change in immunoreactive CYP4A levels was measured. Liver microsomal epoxide hydrolase activity and immunoreactive protein increased 1.7- and 1.4-fold, respectively, in the D5-exposed group. UDPGT activity toward chloramphenicol was induced 1.8-fold, while no change in UDPGT activity toward 4-nitrophenol was seen. These results suggest that the profile for enzyme induction following inhalation exposure of female Fischer-344 rats to D5 vapors is similar to that reported for phenobarbital, and therefore D5 may be described as a weak "phenobarbital-like" inducer.

Inhalation toxicology of decamethylcyclopentasiloxane (D5) following a 3-month nose-only exposure in Fischer 344 rats.

D5 is a low-molecular-weight cyclic siloxane used for industrial and consumer product applications. The objective of the present study was to evaluate the subchronic toxicity of D5 following a 3-month nose-only inhalation exposure. In addition, animals from both sexes of the control and high dose groups were allowed a 4-week recovery period to observe reversibility, persistence, or delayed occurrence of any potential adverse effects. Male and female Fischer 344 rats were exposed for 6 h/day, 5 days/week for 3 months to target concentrations of 0 (30/sex/group), 26 (20/sex/group), 46 (20/sex/group), 86 (20/sex/group), and 224 (30/sex/group) ppm D5. Recovery groups (0 and 224 ppm) comprised 10 rats/sex/group. Body weights and food consumption were monitored at least twice weekly over the course of exposures. Approximately 16 h preceding euthanasia, animals were transferred into metabolism caging for urine collection and were fasted. Rats were anesthetized with pentobarbital and euthanized by exsanguination. Blood was collected for hematological and clinical biochemical analyses. Selected organ weights were measured and a complete set of tissues was taken for histopathological examination. There were several minor changes observed in clinical biochemistry parameters; the most notable was an increase in gamma glutamyl transferase (gamma-GT) in both sexes at the high dose. In females, this effect was dose-related (46-224 ppm) and did not recover upon cessation of exposure. Additionally, there was an decrease in serum lactate dehydrogenase (LDH) observed in females at 86 and 224 ppm which was not resolved during recovery. There was an increase in absolute and/or relative liver weight in rats of both sexes. Taken together, these data suggest that the female rat is more sensitive to the actions of D5 on the liver. Exposure-related increases in absolute and relative lung weights were observed in both sexes at terminal necropsy. This observation was not noted in males in the recovery phase, but was still present in females. Finally, histopathological evidence indicated the primary target organ following D5 inhalation exposure is the lung, with an increase in focal macrophage accumulation and interstitial inflammation in the lungs of male and female rats exposed to 224 ppm D5. This observation did not appear to resolve at the end of a 1-month period of nonexposure. The incidence of these changes was also slightly increased in rats of both sexes exposed to 86 ppm D5. These data suggest that nose-only D5 vapor inhalation provokes minimal changes in the lung which are similar in incidence and severity to spontaneously occurring changes in control animals after nose-only exposures. There were no histopathological findings noted in the livers which support this organ as a target in this study, despite the observed changes in organ weight and in some serum chemistry parameters.

Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study.

Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.

Subchronic inhalation toxicity of 1,1,1,3-tetrachloropropane in rats.

The purpose of this study was to evaluate the inhalation toxicity of 1,1,1,3-tetrachloropropane (TCP), an intermediate in the production of chlorinated silicone fluids. Male and female Sprague-Dawley rats were exposed 6 hr/day, 5 days/week, for 90 days to TCP at concentrations of 0, 25, 75, or 225 ppm (Phase I study) and to 0, 1, 5, or 10 ppm (Phase II study). Phase II of the study was conducted because a no-observed-effect level was not achieved in Phase I. No animals died during the study. Clinical signs of toxicity included oral, nasal, and/or ocular discharge. No statistically significant differences were observed in either body weights or food consumption between exposed and control animals. Clinical pathology did not indicate any treatment-related effects. Absolute and relative liver and kidney weights were increased in male and female rats exposed to 225 ppm TCP, and heart weights were increased in male rats exposed to 225 ppm TCP. The liver and heart weight changes were supported by the findings of microscopic lesions in these organs. These lesions consisted of multifocal/focal myofiber degeneration necrosis with adjacent chronic myocarditis in the heart and multifocal single-cell necrosis in the liver parenchyma. The liver lesions had essentially resolved at the end of a 28-day recovery period but the heart lesions were still present in male rats in the recovery group exposed to 225 ppm TCP. No treatment-related effects were observed in animals exposed to 1, 5, or 10 ppm TCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive and developmental toxicity studies of silicone gel Q7-2159A in rats and rabbits.

Studies reported here assessed the potential adverse effects of silicone gel, Dow Corning Q7-2159A, on general reproduction and fetal development in male and female Charles River CD rats and New Zealand white rabbits. Two control and three treatment groups of 30 male and 30 female rats and 25 female rabbits per group were used in the one-generation reproduction and developmental toxicity studies, respectively. The silicone gel was implanted subcutaneously in two flank sites at dosage levels of 3, 10, and 30 ml/kg. The highest dose was selected on the basis of likely human body burden. Control groups received either sterile saline or carboxymethylcellulose solution in two flank implantation sites. The control and test articles were implanted in male and female rats 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). There were no treatment-related effects on F0 parental general conditions and reproductive performance, F1 neonatal viability, or growth in the rat reproduction study. No maternal nor developmental effects, including teratogenicity, were observed in rabbits in the groups implanted with Q7-2159A gel in the developmental toxicity study.

Reproductive and developmental toxicity studies of silicone elastomer Q7-2423/Q7-2551 in rats and rabbits.

The purpose of these studies was to assess the potential adverse effects of silicone breast implant envelope elastomer on general reproduction and fetal development in rats and rabbits. One control and one treatment group of 30 male and 30 female Charles River CD rats and 25 inseminated New Zealand white rabbits per group were used in the one-generation reproductive and developmental toxicity studies, respectively. Two 1.2-cm discs of silicone elastomer were subcutaneously implanted in one site in the left flank and one site in the right-flank of the treated group of rats, while four 2.5-cm discs were implanted in two sites in the left flank and two sites in the right flank of the treated group of rabbits. The size of the elastomer implants was chosen to approximate the expected body burden of women with breast implants. The control animals in both studies received subcutaneous implantation of either 1.2- or 2.5-cm discs of polyethylene of the same number in the same locations. The control and test articles were implanted in the male and female rats at 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). Subcutaneously implanted discs of silicone breast implant envelope elastomer did not induce maternal or developmental toxicity before or during pregnancy or during lactation, did not cause any adverse effects on the parents or neonates, and did not impair reproductive performance in the rat reproduction study. No maternal toxicity or adverse developmental effects, including teratogenicity, were observed in the treated groups in the rabbit developmental toxicity study.

Blood lead concentrations in hereditary hemochromatosis.

We postulated that patients with hereditary hemochromatosis (HH) absorb increased quantities of lead, as do iron-deficient subjects. To test this hypothesis, whole blood lead concentration ([blood Pb]) was quantified by atomic absorption spectrometry in HH homozygotes (n = 44), obligate heterozygotes (n = 19), normal control subjects (n = 33), and abnormal controls, with transfusion-induced iron overload (n = 8). HH homozygotes had higher [blood Pb] than did normal control subjects (5.6 +/- 0.6 microgram/dl vs 3.6 +/- 0.5 microgram/dl; p < 0.005); significantly increased mean [blood Pb] was observed in both male and female homozygotes. In heterozygotes, the mean [blood Pb] 4.1 +/- 0.5 microgram/dl) was intermediate between that of homozygotes and normal control subjects. The mean [blood Pb] of subjects with transfusion-induced iron overload (22 +/- 0.6 microgram/dl) did not differ significantly from that of normal controls. The findings in homozygotes could to be related to age, serum ferritin concentration, presence or absence of iron loading, or the extent of therapeutic phlebotomy. Lead exposure in all of our subjects was due primarily to ambient sources. Analysis of our data, when using a mathematical biokinetic model of human lead metabolism, suggests that the most likely explanation for our findings is that homozygotes (and, to a lesser extent, heterozygotes) absorb increased quantities of lead, a conclusion that corresponds to the increased absorption of iron and cobalt previously documented in homozygotes.

Increased oxidative stress in the liver of mice treated with trichloroethylene.

In this study the trichloroethylene treatment-associated production of oxidative stress in mouse liver by measurements of changes in oxygen consumption, the disappearance of beta-nicotinamide adenine dinucleotide reduced form (NADPH), and the rate of malondialdehyde formation have been investigated. The treatment of mice with trichloroethylene (TCE), trichloroacetic acid (TCA), a metabolite of TCE, or clofibrate, a peroxisome proliferator, resulted in an increase in the oxygen consumption of liver microsomes compared to the values of the untreated controls. A maximum increase in the level of oxygen consumption in liver microsomes was observed in the mice treated with TCE, followed by clofibrate and TCA treatments. All three agents also increased the rate of NADPH oxidation in mice liver microsomes compared with untreated controls. NADPH oxidation was increased four fold by TCE or clofibrate (38 or 37 nmol/min) and two fold by TCA treatment (17 nmol/min) over that of the control animals (9 nmol/min). The concentration of malondialdehyde was higher in all three treated groups in comparison with control values. Malondialdehyde levels were elevated by 227%, 191%, and 118% by treatment with TCE, clofibrate, and TCA, respectively. Increases in the levels of oxygen consumption, NADPH disappearance, and malondialdehyde production in microsomes from liver of mice treated chronically with TCE or TCA are all indicative of elevated levels of oxidative stress. Increased oxidative stress may be involved in the induction of TCE-associated hepatotoxicity.

Fluorescence microscopy of DES-induced morphologic transformation in unfixed, cultured cells.

Cultured baby Syrian hamster kidney cells (BHK 21), synchronized with hydroxyurea (HU), were treated with varying amounts of the carcinogen diethylstilbestrol (DES) during the first mitosis. DES-induced morphologic transformation was assessed by fluorescence microscopy of acridine orange, supravitally stained cells. Traditional karyotyping techniques were used to monitor DES-induced aneuploidy in parallel cell cultures. A total of 618 photomicrographs were obtained by systematic manual scanning of three replicate experiments each using three different DES treatment levels and a no DES control. These photomicrographs were randomized and graded blind by three independent observers. Each photomicrograph was graded for cellular morphologic transformation and a judgement as to whether DES treatment had been used. A definite dose-response relationship for both morphologic transformation, as well as for aneuploidy was observed. These findings portend a significance for use of fluorescence microscopy of morphologic transformation of unfixed supravitally stained mammalian cells, for the rapid assessment (24 h or less) of compounds that promote aneuploidization and carcinogenesis.

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.

Distribution, metabolism, and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration.

Pregnant CD-1 mice were treated with 20 (i.p.) or 40 (p.o.) mg/kg sodium arsenate on gestation day 18 (plug = day 1). Individual fetuses, pooled placentas and maternal blood, urine, liver, and kidneys were obtained from three or more litters at intervals up to 24 hours following treatment. Acid-digested samples were analyzed for total arsenic by hydride generation atomic absorption spectrophotometry. The rate of arsenic elimination from maternal samples was not influenced by administration route. First-order elimination followed a brief period of distribution, and the biological half-life was approximately 10 hours. Arsenic was found in most samples, with mean peak concentrations expressed as micrograms As/gm (wet wt.) or /ml (values listed are post-treatment sampling times in minutes or hours and concentrations for i.p. and for p.o. treated groups, respectively) as follows: fetuses-2, 3.5; 6, 0.8, placentas-2, 9.3; 1, 2.3, blood-10 minutes, 6.9; 1, 2.0, urine-1, 712; 2, 342, kidney-20 minutes, 25.4; 1, 11.0, liver-0.5, 7.9; 1, 11.7. By 24 hours, arsenic levels in fetuses and placentas had declined to 0.22 microgram/gm and 0.74 microgram/gm for i.p. and 0.33 microgram/gm and 0.57 microgram/gm for p.o. treatments, respectively. Fetal arsenic uptake and loss were more rapid following i.p. than p.o. treatments, and although the i.p. dose was only half that used p.o., peak fetal As+5 was almost fivefold higher following i.p. treatment. These results agree with the finding that oral dosing of pregnant mice with arsenate has less effect on the conceptus than does treatment by injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Subacute toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide, N-2-hydroxyethyl retinamide, and N-4-hydroxyphenyl retinamide.

The major limitation for continuous administration of natural retinoids for chemoprevention of cancer is their high toxicity; however, synthetic retinamides have the desirable quality of reduced toxicity while retaining most of the biological activity. We have presently evaluated the comparative toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide (ER), N-2-hydroxyethyl retinamide (HER), and N-4-hydroxyphenyl retinamide (HPR) in mice and rats after po and ip administration. The computed LD90, DL50, and LD10 values for combined sexes of mice following 21 daily doses of the above retinoids were determined. Identical doses of the same retinoid by ip administration produced more toxicity and deaths than by the po route. The 13-cis-isomers exhibited comparatively less toxicity than the corresponding all-trans-isomer. Based on the lethality data, all-trans-retinoic acid was most toxic followed by all-trans-HER greater than all-trans-HPR greater than all-trans-ER. Changes in clinical chemistry and hematological parameters associated with administration of the retinamides include a dose-dependent peripheral anemia evidenced by erythrocytopenia and decreased hemoglobin concentration and packed cell volume. Retinoid treatment also caused increased plasma alkaline phosphatase activity and decreased serum albumin levels. Histopathological changes associated with retinoid administration primarily included liver lesions as characterized by degeneration and enlargement of hepatocytes. The present studies indicate that synthetic retinoids are less toxic than the natural ones.