Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model

Immature rats are more susceptible than adults to the acute neurotoxicity of pyrethroid insecticides like deltamethrin (DLM). A companion kinetics study (Kim et al., in press) revealed that blood and brain levels of the neuroactive parent compound were inversely related to age in rats 10, 21, 40 and 90 days old. The objective of the current study was to modify a physiologically based pharmacokinetic (PBPK) model of DLM disposition in the adult male Sprague-Dawley rat (Mirfazaelian et al., 2006), so blood and target organ dosimetry could be accurately predicted during maturation. Age-specific organ weights and age-dependent changes in the oxidative and hydrolytic clearance of DLM were modeled with a generalized Michaelis-Menten model for growth and the summary equations incorporated into the PBPK model. The model's simulations compared favorably with empirical DLM time-courses in plasma, blood, brain and fat for the four age-groups evaluated (10, 21, 40 and 90 days old). PND 10 pups' area under the 24-h brain concentration time curve (AUC_0-24h) was 3.8-fold higher than that of the PND 90 adults. Our maturing rat PBPK model allows for updating with age- and chemical-dependent parameters, so pyrethroid dosimetry can be forecast in young and aged individuals. Hence, this model provides a methodology for risk assessors to consider age-specific adjustments to oral Reference Doses on the basis of PK differences.     

Effects of diuron on male rat reproductive organs: a developmental and postnatal study

This study was performed to determine whether developmental exposure (perinatal and juvenile) to the herbicide diuron exerted adverse effects on adult rat male reproductive system. Pregnant Sprague-Dawley rats received basal diet or diet containing diuron at 500 or 750 ppm from gestational day 12 (GD 12) until the end of lactation period (postnatal day 21, PND 21). After weaning male offspring received basal diet or diet containing diuron until PND 42 (peripubertal age). At PND 90, adult male rats from each experimental group were anesthetized and euthanized for evaluation of body and reproductive organ weights, sperm parameters, plasma testosterone levels, and testicular and epididymal histopathology. Male offspring exposed to diuron at 750 ppm displayed reduced body weight at PND 10, 21, 42, and 90 compared to controls. At PND 90, diuron treatment did not induce significant change in daily sperm production, sperm morphology and motility, and testosterone levels compared to controls. In conclusion, diuron at 750 ppm induced male offspring toxicity but these alterations were not permanent, as evidenced by absence of reproductive-system alterations in adult Sprague Dawley rats.     

Assessment of Offspring Development and Behavior Following Gestational Exposure to Inhaled Methanol in the Rat

The prospect of widespread human exposure associated with itsuse as an alternative fuel has sparked concern about the toxicpotential of inhaled methanol (MeOH). Previous studies haverevealed congenital malformations in rats following inhaledMeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5,727–736)but these studies did not include postnatal behavioral assessment.In the present study, pregnant Long–Evans rats were placedin exposure chambers containing 15,000 ppm MeOH or air for 7hr/day on Gestational Days (GD) 7–19. The total alveolardose of methanol was estimated at about 6.1 g/kg/day, for atotal dose of about 42.7 g/kg for the entire study. Maternalbody weights were recorded daily and blood methanol concentrationswere determined at the end of exposure on GD 7, 10, 14, and18. Following birth (Postnatal Day 0 [PND 0]), a number of testswere performed at various points in development, including:offspring mortality and body wt (PND 1, 3), motor activity (PND13–21, 30, 60), olfactory learning (PND 18), behavioralthermoregulation (PND 20–21), T-maze learning (PND 23–24),acoustic startle response (PND 24, 60), reflex modfficationaudiometry (PND 60), pubertal landmarks (PND 31–56), passiveavoidance (PND 72), and visual-evoked potentials (PND 160).Maternal blood MeOH levels, measured from samples taken within15 mm after removal from the exposure chamber, declined fromabout 3.8 mg/ml on the first day of exposure to 3.1 mg/ml onthe 12th day of exposure. MeOH transiently reduced maternalbody wt (4–7%) on GD 8–10, and offspring BW (5%)on PND 1. No other test revealed significant effects of MeOH.Prenatal exposure to high levels of inhaled MeOH appears tohave little effect on this broad battery of tests beyond PND1 in the rat.     

Concentration and persistence of tin in rat brain and blood following dibutyltin exposure during development

Dibutyltin (DBT), a widely used plastic stabilizer, has been detected in the environment as well as human tissues. Although teratological and developmental effects are well documented, there are no published reports of DBT effects on the developing nervous system. As part of a developmental neurotoxicity study of DBT, tissue samples were periodically collected to determine the distribution of total tin (Sn) in brain and whole blood. Pregnant Sprague-Dawley rats were exposed to 0, 10, or 25 ppm DBT in drinking water from gestational day (GD) 6 to weaning at postnatal day (PND) 21. Beginning on PND 3, half of the litters were directly dosed every 2 to 3 d via oral gavage with 0, 1, or 2.5 mg/kg DBT such that the dose level matched the water concentration (for example, litters with 25 ppm DBT in the water received 2.5 mg/kg). For Sn analysis, brain and blood samples were collected from culled pups on PND2 (males and females pooled), from pups (males and females separately) as well as dams at weaning (PND21), and from adult offspring (males and females) at PND93. Total Sn was quantified using inductively coupled plasma-mass spectroscopy (ICP-MS). At all ages, brain Sn levels were higher than blood. At culling, in the directly dosed pups at weaning, and in dams at weaning, Sn levels in both tissues were linearly related to dose. Weanling pups without direct dosing showed lower levels than either culled pups or dams, indicating that lactational exposure was minimal or negligible even while maternal exposure is ongoing. In the adults, Sn levels persisted in brains of directly dosed rats, and the high-dose females had higher levels than did high-dose males. No Sn was detected in adult blood. Thus, during maternal exposure to DBT in drinking water, Sn is placentally transferred to the offspring, but lactational transfer is minimal, if any. Furthermore, Sn is concentrated in brain compared to blood, and its elimination is protracted, on the order of days to months after exposure ends.     

Serum bisphenol A pharmacokinetics and prostate neoplastic responses following oral and subcutaneous exposures in neonatal Sprague-Dawley rats

The present study examines BPA pharmacokinetics in neonatal rats following s.c. injection or oral delivery of 10 μg BPA/kg BW and compares susceptibility to estrogen-induced prostate intraepithelial neoplasia (PIN) following either exposure route. Serum BPA in PND3 rats was measured using HPLC-MS-MS. Free and total BPA at C(max) were 1.77 and 2.0 ng/ml, respectively following injection and 0.26 and 1.02 ng/ml, respectively following oral exposure. The AUC(0-2) for free and total BPA was 4.1-fold and 1.8-fold greater, respectively, in s.c. vs. oral delivery. While exposure route affected BPA metabolism, internal dosimetry following s.c. injection of 10 μg BPA/kg BW is similar to BPA levels observed in humans. Prostates from aged rats given s.c. or oral BPA neonatally and T+E implants as adults exhibited nearly identical, heightened susceptibility to PIN incidence and score as compared to neonatal oil-controls. These findings on prostate health are directly relevant to humans at current BPA exposure levels.     

Effect of conazole fungicides on reproductive development in the female rat

Three triazole fungicides were evaluated for effects on female rat reproductive development. Rats were exposed via feed to propiconazole (P) (100, 500, or 2500 ppm), myclobutanil (M) (100, 500, or 2000 ppm), or triadimefon (T) (100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 98. Body weight (BW) and anogenital distance (AGD) at PND 0, age and BW at vaginal opening (VO), estrous cyclicity, and body and organ weight at necropsy were measured. BW at PND 0 was unaffected by treatment. AGD was increased by M2000. VO was delayed by M2000 and T1800. Estrous cyclicity was initially disrupted by P500, P2500 and T1800, but later normalized. At PND 99 there was a decrease in BW by T1800, an increase in liver weight by P2500 and T1800, and an increase in ovarian weight by M2000 and T1800. It is concluded that exposure to P, M and T adversely impacted female rodent reproductive development.     

Effect of conazole fungicides on reproductive development in the female rat

Three triazole fungicides were evaluated for effects on female rat reproductive development. Rats were exposed via feed to propiconazole (P) (100, 500, or 2500 ppm), myclobutanil (M) (100, 500, or 2000 ppm), or triadimefon (T) (100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 98. Body weight (BW) and anogenital distance (AGD) at PND 0, age and BW at vaginal opening (VO), estrous cyclicity, and body and organ weight at necropsy were measured. BW at PND 0 was unaffected by treatment. AGD was increased by M2000. VO was delayed by M2000 and T1800. Estrous cyclicity was initially disrupted by P500, P2500 and T1800, but later normalized. At PND 99 there was a decrease in BW by T1800, an increase in liver weight by P2500 and T1800, and an increase in ovarian weight by M2000 and T1800. It is concluded that exposure to P, M and T adversely impacted female rodent reproductive development.     

Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure

The purpose of this study was to evaluate the relative sensitivity of neonatal and adult CD rats to manganese-induced neurotoxicity. Identical oral manganese chloride (MnCl(2)) doses (0, 25, or 50 mg kg(-1) body wt. day(-1)) were given to neonatal rats throughout lactation (i.e. from postnatal day (PND) 1 through 21) and to adult male rats for 21 consecutive days. The MnCl(2) doses administered to neonates were ca. 100-fold higher than those resulting from the consumption of an equivalent volume of rat's milk. Rats were assessed using similar behavioral and neurochemical evaluations. Several statistically significant changes occurred in Mn-exposed rats relative to control animals. Neonates given the high dose of MnCl(2) had reduced body weight gain. An increased pulse-elicited acoustic startle response amplitude was observed in neonates from both MnCl(2) treatment groups on PND 21. Increased striatal, hippocampal, hindbrain and cortical Mn concentrations were observed in all Mn-exposed neonates on PND 21. Increased hypothalamic and cerebellar Mn concentrations were also observed on PND 21 in neonates from the high-dose group only. Increased striatal, cerebellar and brain residue Mn concentrations were observed in adult rats from the high-dose group. Increased striatal dopamine and 3,4-dihydroxyphenylacetic acid levels were observed only in PND 21 neonates from the high-dose group. No treatment-related changes were observed in clinical signs, motor activity (assessed in neonates on PND 13, 17, 21 +/- 1 and in adults), passive avoidance (assessed in neonates on PND 20 +/- 1 and in adults) or neuropathology (assessed in PND 21 neonates only). The results of our experiment suggest that neonates may be at greater risk for Mn-induced neurotoxicity when compared to adults receiving similar high oral levels of Mn.     

Lack of maternal dietary exposure effects of bisphenol A and nonylphenol during the critical period for brain sexual differentiation on the reproductive/endocrine systems in later life

Two potential endocrine-disrupting chemicals, bisphenol A (BPA) and nonylphenol (NP), were assessed for their long-lasting effects on endocrine/reproductive systems following transplacental and lactational exposure to rat offspring during a time-window that included the critical period for brain sexual differentiation. Each chemical was mixed with diet at concentrations of 60, 600 and 3000 ppm and was provided to maternal Sprague-Dawley rats from gestational day (GD) 15 to postnatal day (PND) 10. Ethinylestradiol (EE) at 0.5 ppm was used as an estrogenic reference drug. During pregnancy and lactation, including the exposure period, a soy-free rodent diet was provided to eliminate possible modification of the study results by plant-derived phytoestrogens. Effects on endocrine/reproductive systems were evaluated by examining the anogenital distance, organ weights before puberty, onset of puberty, estrous cyclicity, and organ weights and histopathology of adult endocrine organs (at 11 weeks of age), as well as the volume of the sexually dimorphic nucleus of preoptic area. Both NP and BPA, at high doses, caused decreases in maternal body weights and retardation of offspring growth, but neither affected any of the endocrine/reproductive endpoints of offspring, whereas EE induced irreversible changes in estrous cyclicity and histopathology of ovaries and uterus of adult females. The results indicated that maternal dietary exposure to NP or BPA at concentrations up to 3000 ppm from GD 15 through PND 10 do not exert any apparent adverse effects on the endocrine/reproductive systems of offspring.     

Disposition of Butadiene Epoxides in Sprague-Dawley Rats Following Exposures to 8000 ppm 1,3-Butadiene: Comparisons with Tissue Epoxide Concentrations Following Low-Level Exposures

1,3-Butadiene (BD), a compound used extensively in the rubberindustry, is weakly carcinogenic in Sprague-Dawley rats afterchronic exposures to concentrations of 1000 and 8000 ppm. Conversely,in B6C3F1 mice, tumors occur after chronic exposures to concentrationsas low as 6.25 ppm. Previously, we have shown that tissue concentrationsof the mutagenic BD metabolites, butadiene monoepoxide (BDO)and butadiene diepoxide (BDO₂), are present in greater concentrationsin mice than in rats following acute exposures to low levels(100 ppm or less). This disparity was particularly significantfor the diepoxide. We hypothesized that if these epoxides areinvolved in the carcinogenic response of BD, then they willalso be present in rat tissues at relatively high concentrationsfollowing exposures to 8000 ppm BD. In the present study, concentrationsof the BD epoxides, BDO and BDO₂, were determined in blood offemale Sprague-Dawley rats following a single 6-h exposure and10 repeated exposures to a target concentration of 8000 ppmBD. Concentrations of these epoxides were also determined ina number of other tissues, including the primary rat targetorgan—mammary gland—following 10 repeated exposures.Blood concentrations of BDO were 4030 pmol/g ± 191 followinga 6-h exposure and were 18% lower following the 10-day exposure.Blood concentrations of BDO₂, following the 8000 ppm exposures,were very similar to those previously observed after exposuresto 62.5 ppm BD (11 ± 1 and 17 ± 1 pmol/g followingexposures of 6h and 6h/day for 10 days, respectively.) Concentrationsof BDO ranged from 740 ± 110 (femur) to 8990 ±1150 (fat) pmol/g tissue. Concentrations of BDO₂ were similaramong eight tissues analyzed, ranging from 5 ± 1 (femur)to 17 ± 3 (heart) pmol/g tissue. Tissue concentrationsof butadiene mono-epoxide were increased by 17- to 50-fold intissues from rats exposed by inhalation to 8000 ppm BD as comparedto tissues from rats exposed to 62.5 ppm BD. Based on earlierstudies at our institute the internal dose of BD increases approximately14-fold in the 8000 ppm-exposed rats compared to rats exposedto 62.5 ppm BD. Concentrations of butadiene diepoxide in rattissues following an exposure to 8000 ppm BD were similar tothose observed in rat tissues following exposures to 62.5 ppmBD. This study shows that pathways responsible for the accumulationof BDO₂ in rats are saturated following low-level BD exposures.This suggests that the primary determinant of BD tumorigenicityin rats is not butadiene diepoxide. The high levels of BDO observedin rat mammary tissue suggest that this metabolite may be amore important determinant of BD carcinogenesis in the rat.     

Metabolic interaction and disposition of methyl ethyl ketone and m-xylene in rats at single and repeated inhalation exposures

1. Rats were exposed to m-xylene (300 ppm) and methyl ethyl ketone (MEK, 600 ppm) vapour, separately and in combination. 2. Repeated exposures to m-xylene enhanced liver drug-metabolizing capacity, whereas MEK showed no effects. After mixed exposure the cytochrome P-450-dependent monooxygenase activities were additively or synergistically induced. 3. In the presence of MEK the overall metabolism of xylene was strongly inhibited both after single and repeated exposures, an effect accompanied by elevation of xylene concentration in blood (18-29%) and fat (25-32%). 4. The 24-h excretion of the urine metabolites of m-xylene was decreased by 22-24% in mixed exposures: the excretion of methylhippuric acid was decreased (29%), but that of 2,4-dimethylphenol increased (9-35%). 5. After repeated inhalation exposures the excretion of xylene metabolites in urine was consistently higher, whereas the concentrations of xylene in fat (but not the concentration of MEK) were lower than after a single treatment, conceivably due to accelerated metabolic clearance of xylene. 6. Thioether excretion in urine was enhanced in xylene-treated rats (7-13-fold), but was not influenced by the induced changes in the metabolism of xylene. Xylene inhalation caused liver GSH to decrease slightly (10%), as did inhalation of MEK, but the latter did not enhance the excretion of thioethers. 7. MEK is a potent inhibitor of the side-chain oxidation of m-xylene producing methylhippuric acid, but not of its ring oxidation to 2,4-dimethylphenol, and exhibits a synergistic inducing effect on liver enzymes responsible for the oxidation of m-xylene. The increased ring oxidation of m-xylene was not associated with increased production of reactive metabolites indicated by GSH-depletion or thioether formation.     

Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats

Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200?ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200?ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200?ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.     

Tissue-specific and dose-related accumulation of arsenic in mouse offspring following maternal consumption of arsenic-contaminated water

The developmental toxicity of arsenic is not as well characterized as other metals such as lead or mercury. Many previous animal studies have used an acute exposure paradigm, which does not model chronic, low-level human exposure. The following study administered 10, 20, 40, 80 or 100 ppm sodium arsenite in drinking water to pregnant C57BL6/J mice. Adipose, blood, brain, breastmilk in stomach, kidney and liver tissues were collected from male and female offspring on postnatal day (PND) 1 and 21 to allow for disposition comparisons between tissues, sexes and across time. The 100 ppm dose was foetotoxic. Significantly fewer female pups were born in litters exposed to 80 ppm, while significantly more male pups were born in litters exposed to 20 ppm. Total arsenic levels differed between tissues with the highest levels in the brain and kidney in PND1 offspring. Levels were higher on PND1 than PND21, and there were few sex differences. The dose-response relationships in PND1 tissues were curvilinear, but in PND21 liver and kidney tissues, arsenic levels in control animals were significantly higher than levels in exposed animals. The tissue and age-specific disposition suggests that common biomarkers such as blood and urinary arsenic are not accurate predictors of levels in sensitive organs such as the brain.     

Effects of photomirex and mirex on reproduction in the rat

Groups of weanling male and female rats were fed diets containing photomirex at levels of 0, 2.5, 5.0, 10, 20, or 40 ppm or mirex at 5.0, 10, 20, or 40 ppm for a period of 91 days prior to mating, 15 days during mating, and throughout gestation and lactation. Females fed 40 ppm photomirex or mirex diet showed a significant decrease in weight gain but not in food consumption. Both chemicals at levels of 5.0 ppm and up resulted in a decreased incidence of females showing sperm in vaginal smears. While the litter size was decreased in all treatment groups, the survival indices of pups were affected only by 40 ppm photomirex and 20 ppm mirex. On necropsy, enlarged livers were observed in adult females treated with 40 ppm of photomirex or mirex. Hepatic microsomal aminopyrine demethylase activities were increased in all treated groups of females as well as their offsprings. Minor biochemical changes in serum included elevated levels of cholesterol and total protein of female rats fed 40 ppm photomirex. Residue analysis showed that both chemicals accumulated in a dose-dependent manner in the fat and livers of the adult females, and in the livers of rat pups. None of the hematological parameters were affected by treatment. Histopathologic changes were observed in the livers and thyroids of mothers and pups from all treatment groups. Both photomirex and mirex caused cataract formation in the pups.     

Differential effects of adult and perinatal lead exposure on morphine-induced locomotor activity in rats

The effects of adult and perinatal lead treatment on the development of locomotor sensitization produced with repeated morphine administration was investigated. In Experiment 1, adult male rats received a diet containing 250 ppm lead acetate or a control diet for 43 days. Animals then received 10 mg/kg morphine sulfate or water vehicle (ip) and locomotor activity was monitored for 14 consecutive days. While both control and lead-exposed animals demonstrated a locomotor sensitization to morphine, the magnitude of the increased locomotor response was reduced in lead-treated animals. Subsequent analysis of blood-lead in the adult lead-exposed animals indicated residue levels ranging between 20 and 30 microg/dl. In Experiment 2, adult female rats were treated daily with 0, 8, or 16 mg lead via gavage for 30 days before breeding with non-exposed males. Lead exposure in dams continued through gestation and until pups were weaned at postnatal day (PND) 21. At PND 60, male offspring received morphine or vehicle challenges identical to those described in Experiment 1. Animals perinatally exposed to dams receiving 16 mg lead daily demonstrated an enhanced behavioral response to morphine relative to control animals. Analysis of offspring blood indicated lead levels below detectable limits (<1 microg/dl) for all animals. The results suggest exposure to lead at environmentally relevant levels produces long-lasting changes in drug-induced behavior, and the developmental period in which lead exposure occurs is a significant contributor to the manifestation of these effects.     

Ontogeny of behavioral sensitization to cocaine

The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56–60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21–25 or 28–32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later.     

Development of a physiologically based pharmacokinetic model of organic solvent in rats.

A physiologically based pharmacokinetic model of the transfer of organic solvents in rat bodies was developed. The model has six compartments, i.e. lungs, vessel-rich tissue, muscles, fat tissue, tail, and liver, each being interconnected by the blood flow system. The transfer of organic solvents was expressed by simultaneous differential equations, which were then solved numerically by a personal computer using a simple spreadsheet program. m -xylene was used to represent organic solvents. The physiological parameters for rats (alveolar ventilation, cardiac output, tissue volume, tissue blood flow, etc.) and physicochemical or biochemical properties (blood/air partition coefficient, tissue/blood partition coefficients, metabolic constants, etc.) of m -xylene were based on the data obtained from the literature and our experiments. The partition coefficient of m -xylene for the tail and the blood flow and the volume of the rat tail were experimentally determined with adult rats. The results of simulation of rat exposure to m -xylene (50 and 500 ppm for 6 h) were essentially in good agreement with the experimental data on rats, i.e. the parent compound (m -xylene) concentration in the tail blood and the cumulative excretion of the metabolites in the urine were consistent.     

Organotin speciation and tissue distribution in rat dams, fetuses, and neonates following oral administration of tributyltin chloride

Tributyltin (TBT) is a biocide that contaminates human foodstuffs, especially shellfish. TBT is an endocrine disrupter, producing imposex in several marine gastropods. Previous studies showed that oral dosing of rat dams with TBT chloride leads to abnormal fetal and postnatal development. In this study, the tissue distribution and speciation of organotins in tissues were examined in dams, fetuses, and neonates following dosing of rat dams commencing on gestational day (GD) 8 by oral gavage with TBT in olive oil at 0, 0.25, 2.5, or 10 mg/kg body weight (BW)/d. Dams' body weights were significantly reduced by the 10-mg/kg BW/d TBT treatment. At GD20, there were no significant effects of any TBT treatment on pup weights, litter size, sex ratio, or tissue weights. However, at postnatal day (PND) 6 and 12, neonatal pup weights were reduced by the 10-mg/kg BW/d TBT treatment but tissue weights were unaffected, except for the liver weight of female pups, which was reduced by the 10-mg/kg BW/d TBT treatment. Tissues harvested on GD20 and PND6 and PND12 were extracted for determination of organotins by gas chromatography-atomic emission detection (GC-AED). In most tissues, TBT and its metabolite dibutyltin (DBT) were evident but monobutyltin (MBT) was rarely measured above the detection limit. The livers and brains of fetuses contained TBT and DBT at levels that were approximately 50% of the equivalent tissues in the dams. Furthermore, these tissues appeared to preferentially absorb/retain organotins, since the concentrations were greater than were found for the total loading in whole pups. The placenta also contained relatively large quantities of TBT and DBT. Postnatally, the TBT levels in pups decreased markedly, a probable consequence of the extremely low levels of organotins in rat milk. However, DBT levels in pups livers and brains were maintained, probably due to metabolism of TBT to DBT. Similarly, while dams' spleens contained significant quantities of organotins, the pups' spleens contained smaller quantities, and these decreased rapidly between PND6 and PND12. These results show that organotins cross the placenta and accumulate in fetal tissues but that during lactation, the pups would receive minimal organotins through the milk and during this period, the levels of TBT in pups' tissues decreases rapidly. Consequently, fetuses would be at greater risk of the adverse effects of TBT, but due to the lack of transfer through milk, the risk would be reduced during the lactational period.     

Role of Kinetics in Acute Lethality of Nonreactive Volatile Organic Compounds (VOCs)

The role of kinetics in the acute inhalation toxicity of nonreactive,volatile organic compounds (VOCs), including lipophilic andhydrophilic compounds, was analyzed with a physiologically basedpharmacokinetic (PB-PK) model for the rat. For 15 VOCs, a totalof 23 LC50 values were retrieved from the literature. It wasobserved that the external exposure parameter (LC50·exposurelength; in ppm · h), varied approximately 60-fold Concentrationsof compounds in the lipoid brain fraction were simulated usinga kinetic model. This lead to a more than 10-fold reductionin the toxic range of the 15 VOCs. The average value for thissimulated dose surrogate was 70±31 mM for all VOCs. Theseobservations support the presumption that nonspecific, acutenarcotic lethality is directly related to the extent of VOCdistribution into lipoid brain constituents. The present resultscan be used for estimation of the acute lethality of nonreactiveVOCs on the basis of kinetic simulations. In addition, the presentlycalculated dose surrogate for VOC lethality in rats is foundto be very similar to the reported internal lethal concentrationsof so-called "baseline toxicity compounds" in fish. This indicatesa common mechanism of acute VOC toxicity among mammalian andaquatic species.