OECD 414 supplementary prenatal developmental toxicity study of sodium molybdate dihydrate in the rat and benchmark dose evaluation.

In a continuing investigation of the potential for reproductive and developmental toxicity of molybdenum (Mo), consequent to the previous published OECD studies [1,2] and as directed by the European Chemicals Agency [3], a supplemental rat GLP-compliant Prenatal Developmental Toxicity (PNDT) study was conducted to investigate higher dose levels of sodium molybdate dihydrate (SMD) in an identical study design (OECD 414)[4] to Murray et al. 2014a [1], at dietary concentrations calculated to provide target Mo levels of 80 and 120 mg/kg bw/day (the maximum-tolerated dose). There was no effect on post-implantation loss, litter size, sex ratio or the incidence of external, visceral or skeletal fetal malformations or variations. Fetal weight was reduced proportionate to maternal dose. Minimal differences observed in the ossification status of some extremities of fetuses from females receiving 120 mg Mo/kg bw/day were confirmed as transient by skeletal examination of PND 21 pups from a further group of females receiving the same dose regime. There was no evidence of copper depletion in serum, placenta or liver. A benchmark dose evaluation using continuous and dichotomous approaches by combining the fetal body weight data from this study and the previous study determined that the BMD05 ranged from 47 to 57 mg Mo/kg bw/day, depending on the modelling approach and the BMDL05 estimates ranged from 37 to 47 mg Mo/kg bw/day. These levels are considered a more statistically robust point of departure for risk assessment for reproductive effects than the established NOAEL of 40 mg Mo/kg bw/day.

Health assessment of gasoline and fuel oxygenate vapors: developmental toxicity in mice.

CD-1 mice were exposed to baseline gasoline vapor condensate (BGVC) alone or to vapors of gasoline blended with methyl tertiary butyl ether (G/MTBE). Inhalation exposures were 6h/d on GD 5-17 at levels of 0, 2000, 10,000, and 20,000mg/m(3). Dams were evaluated for evidence of maternal toxicity, and fetuses were weighed, sexed, and evaluated for external, visceral, and skeletal anomalies. Exposure to 20,000mg/m(3) of BGVC produced slight reductions in maternal body weight/gain and decreased fetal body weight. G/MTBE exposure did not produce statistically significant maternal or developmental effects; however, two uncommon ventral wall closure defects occurred: gastroschisis (1 fetus at 10,000mg/m(3)) and ectopia cordis (1 fetus at 2000mg/m(3); 2 fetuses/1 litter at 10,000mg/m(3)). A second study (G/MTBE-2) evaluated similar exposure levels on GD 5-16 and an additional group exposed to 30,000mg/m(3) from GD 5-10. An increased incidence of cleft palate was observed at 30,000mg/m(3) G/MTBE. No ectopia cordis occurred in the replicate study, but a single observation of gastroschisis was observed at 30,000mg/m(3). The no observed adverse effect levels for maternal/developmental toxicity in the BGVC study were 10,000/2000mg/m(3), 20,000/20,000 for the G/MTBE study, and 10,000/20,000 for the G/MTBE-2 study.

The effect of pregnancy on renal clearance of boron in humans: a study based on normal dietary intake of boron.

Boron occurs most frequently in nature as borates and boric acid, never as the free element. Its largest uses are in glass, detergents, and agriculture. Essential for higher plants, there is growing evidence for essentiality in vertebrates. Humans consume daily about a milligram of boron, mostly from fruit and vegetables. At high doses, boron is a developmental and reproductive toxin in animals. Pregnant rats were the most sensitive. An oral NOAEL of 9.6 mg B/kg/day was established for developmental toxicity in Sprague-Dawley rats fed boric acid. To extrapolate from the large, animal boron toxicity database to humans, especially to pregnant women, information on renal clearance of boron was needed. This study's purpose was to measure renal clearance of boron in pregnant and nonpregnant woman. In 16 second trimester women and 15 nonpregnant age-matched referents, dietary boron provided the blood and urine boron concentrations used for calculating boron clearance. The pregnant and nonpregnant boron intake was 1.35 and 1.31 mg boron/24 h, respectively. Blood for boron, creatinine, and urea was collected at the start, at 2 h, and at 24 h. Urine was collected during the first 2 h in the Clinical Research Center and during a 22-h period outside the center for measurement of volume, boron, and creatinine. Renal boron clearance measured over the initial 2 h, the most complete urine collection period, was 68.30ml/min/1.73 m(2) for pregnant subjects and 54.31ml/min/1.73 m(2) for nonpregnant subjects. Comparison of renal boron clearance with creatinine clearance indicated that tubular reabsorption of boron occurred in both pregnant and nonpregnant women.

The effect of pregnancy on renal clearance of boron in rats given boric acid orally.

Boric acid (H(3)BO(3)) has been shown to cause developmental abnormalities in the offspring of pregnant rats. Comparative data on the renal clearance of boron (B) in rats and humans, both pregnant and nonpregnant, exposed to boric acid (BA) would reduce uncertainty in interspecies extrapolation from rats to humans. The purpose of this study was to evaluate the effect of pregnancy on the plasma half-life and renal clearance of boron in Sprague-Dawley rats given a single oral dose of boric acid. For the half-life study, nonpregnant and pregnant (gestation day 16) rats were given a single dose of 30 mg/kg of boric acid by gavage, and plasma samples were collected at 2-3 h intervals. The plasma half-life of boron was determined to be 2.9 +/- 0.2 and 3.2 +/- 0.3 h in nonpregnant and pregnant rats, respectively. In the clearance study, nonpregnant and pregnant (GD 16) rats were given a single gavage dose of 0.3, 3, or 30 mg/kg of boric acid. Boron clearance was slightly higher in pregnant rats (3.3 +/- 0.6, 3.2 +/- 0.5, and 3.4 +/- 0.5 ml/min/kg, respectively) compared to nonpregnant rats (3.1 +/- 0.8, 3.0 +/- 0.6, and 3.2 +/- 0.5 ml/min/kg, respectively), but the difference was not statistically significant and not dose-related. Boron clearance was less than creatinine clearance, suggesting tubular reabsorption in both groups. In conclusion, pregnancy did not appear to significantly alter the renal clearance or the plasma half-life of boron in Sprague-Dawley rats under the conditions of this study.

Chronic feeding of a low boron diet adversely affects reproduction and development in Xenopus laevis.

The aims of this work were as follows: 1) to determine whether a purified diet currently used for studies with rats was acceptable for reproductive studies in frogs; and 2) to determine whether frogs are sensitive to a deficit of boron (B) in the diet. Adult Xenopus laevis were fed a nonpurified beef liver and lung (BLL) diet (310 microg B/kg), a purified diet supplemented with boron (+B; 1850 microg B/kg), or a purified diet low in boron (-B; 45 microg B/kg) for 120 d. Frogs fed the BLL and +B diets produced 11.3 and 12.2% necrotic eggs, respectively. Abnormal gastrulation occurred in <4% of the fertilized eggs in both groups, and 96-h larval survival exceeded 75% in both groups. In contrast, frogs fed the -B diet for 120 d produced a high proportion of necrotic eggs (54%). Fertilized embryos from the -B diet-fed frogs showed a high frequency of abnormal gastrulation (26.8%), and >80% of the embryos died before 96 h of development. Mean embryo cell counts at X. laevis developmental stage 7.5 (mid-blastula) were significantly lower in the -B embryos than in the BLL or +B embryos. BLL and -B embryos grown in low boron culture media had a high frequency of malformations compared with embryos grown in boron-supplemented media. These studies show that a purified diet that has been used in rodent studies was acceptable for reproduction studies in X. laevis. This work also demonstrates that a diet low in boron markedly impairs normal reproductive function in adult X. laevis, and that administration of the low boron diet results in an increase in both incidence and severity of adverse effects. In addition, these studies demonstrate the usefulness of the X. laevis model in nutrition studies.

An assessment of the views held by recent graduates on their undergraduate course.

The aim of this study was to ascertain the views of recent graduates on their undergraduate training. 53 Vocational Training scheme organisers were contacted and 37 (70%) responded 391 new dentists on the schemes were sent postal questionnaires to record information on their views of the undergraduate dental curriculum, 247 questionnaires were returned giving a response rate of 63%. 62% of the subjects reported that they had received sufficient practical experience in the provision of crowns, 32% for veneers and 19% for bridgework. 46% of respondents felt able to treat a simple orthodontic case with removable appliances. 63% considered they had insufficient experience in surgical extractions, 40% expressed the opinion that overall, they would like more practical clinical experience included in the undergraduate course particularly in crown/bridgework and surgical extractions. In conclusion, there are areas in which recent graduates consider their undergraduate course to have been lacking.

Evaluation of the developmental toxicity of caffeine and caffeine metabolites using the frog embryo teratogenesis assay--Xenopus (FETAX).

The developmental toxicities of caffeine and 13 metabolites, including theophylline, and paraxanthine and a synthetic methylxanthine analogue 3-isobutyl-methylxanthine (IBMX) were evaluated using the Frog Embryo Teratogenesis Assay Xenopus (FETAX). Young X. laevis embryos were exposed to these compounds in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS). Results obtained from these studies indicated that relative teratogenic potencies of caffeine and each of its di- and monomethylxanthine metabolites were similar. Representatives of both the substituted uric and uracil metabolites were less developmentally toxic on an equimolar basis than the methylxanthines, suggesting that they may have represented detoxification metabolites. IBMX, a phosphodiesterase inhibitor also known to be an adenosine receptor antagonist, was the most potent developmental toxicant of the materials evaluated. In conclusion, none of the caffeine metabolites tested was found to be significantly more potent than caffeine itself in the FETAX assay.

Adverse reproductive and developmental effects in Xenopus from insufficient boron.

Frog embryo teratogenesis assay--Xenopus (FETAX) was utilized as a model system to evaluate the effects on embryo-larval development at various low boron (B) exposure levels in the culture media. Concentrations tested ranged from < 1 to 5000 microg B/L. A statistically significant (P < 0.05) increase in malformations was observed at < or = 3 microg B/L, but not at the greater concentrations. Abnormal development of the gut, craniofacial region and eye, visceral edema, and kinking of the tail musculature (abnormal myotome development) and notochord were observed. In subsequent studies, adult frogs were maintained for 28 d on two diets: (1) low B (LB, 62 microg B/kg) or (2) boric acid supplemented (BA, 1851 microg B/kg); the frogs were subsequently mated, and their offspring were cultured in media containing various levels of B. Results of the 28-d depletion studies indicated that frogs maintained under LB conditions produced a greater proportion of (1) necrotic eggs and (2) fertilized embryos, which abnormally gastrulated at a greater rate and were substantially less viable than embryos from frogs fed the BA diet. Malformations similar to those seen in the initial study were observed in embryos from the B-depleted adults maintained in an LB environment; 28 d on the LB diet enhanced the incidence of malformations associated with the LB culture media. These abnormalities were not observed in embryos cultured in > or = 4 microg B/L from adults cultured on the BA diet. These studies showed that insufficient B reproducibly interfered with normal Xenopus laevis development during organogenesis, substantially impaired normal reproductive function in adult frogs, and thus represent the first studies demonstrating the nutritional essentiality of B in an amphibian species.

Assessing the effects of low boron diets on embryonic and fetal development in rodents using in vitro and in vivo model systems.

To date, boron (B) essentiality has not been conclusively shown in mammals. This article summarizes the results of a series of in vitro and in vivo experiments designed to investigate the role of B in mammalian reproduction. In the first study, rat dams were fed either a low (0.04 microg B/g) or an adequate (2.00 microg B/g) B diet for 6 wk before breeding and through pregnancy; reproductive outcome was monitored on gestation day 20. Although low dietary B significantly lowered maternal blood, liver, and bone B concentrations, it had no marked effects on fetal growth or development. The goal of the second study was to assess the effects of B on the in vitro development of rat postimplantation embryos. Day 10 embryos collected from dams fed either the low or adequate B diets for at least 12 wk were cultured in serum collected from male rats exposed to one of the two dietary B treatments. Dams fed the low B diet had a significantly reduced number of implantation sites compared to dams fed the B-adequate diet. However, embryonic growth in vitro was not affected by B treatment. The aim of study 3 was to define the limits of boric acid (BA) toxicity on mouse preimplantation development in vitro. Two-cell mouse embryos were cultured in media containing graded levels of BA (from 6 to 10,000 microM). Impaired embryonic differentiation and proliferation were observed only when embryos were exposed to high levels of BA (>2000 microM), reflecting a very low level of toxicity of BA on early mouse embryonic development. Study 4 tested the effects of low (0.04 microg B/g) and adequate (2.00 microg B/g) dietary B on the in vitro development of mouse preimplantation embryos. Two-cell embryos obtained from the dams were cultured in vitro for 72 h. Maternal exposure to the low B diet for 10, 12, and 16 wk was associated with a reduction in blastocyst formation, a reduction in blastocyst cell number, and an increased number of degenerates. Collectively, these studies support the concept that B deficiency impairs early embryonic development in rodents.

A comparative review of the pharmacokinetics of boric acid in rodents and humans.

The pharmacokinetics of boric acid (BA) have been studied in animals and humans. Orally administered BA is readily and completely absorbed in rats, rabbits, and humans, as well as other animal species. In animals and humans, absorbed BA appears to be rapidly distributed throughout the body water via passive diffusion. Following administration of BA, the ratio of blood: soft tissue concentrations of boron (B) is approx 1.0 in rats and humans; in contrast, concentrations of B in bone exceed those in blood by a factor of approx 4 in both rats and humans. In rats, adipose tissue concentrations of B are only 20% of the levels found in blood and soft tissues; however, human data on adipose tissue levels are not available. BA does not appear to be metabolized in either animals or humans owing to the excessive energy required to break the B-O bond. BA has an affinity for cis-hydroxy groups, and it has been hypothesized to elicit its biological activity through this mechanism. The elimination kinetics of BA also appear to be similar for rodents and humans. BA is eliminated unchanged in the urine. The kinetics of elimination were evaluated in human volunteers given BA orally or intravenously; the half-life for elimination was essentially the same (approx 21 h) by either route of exposure. In rats, blood and tissue levels of B reached steady-state after 3-4 d of oral administration of BA; assuming first-order kinetics, a half-life of 14-19 h may be calculated. The lack of metabolism of BA eliminates metabolic clearance as a potential source of interspecies variation. Accordingly, in the absence of differences in metabolic clearance, renal clearance is expected to be the major determinant of interspecies variation in pharmacokinetics. Because glomerular filtration rates are slightly higher in rats than in humans, the slight difference in half-lives may be readily explained. The most sensitive toxicity end point for BA appears to be developmental toxicity in rats, with a No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) of 55 and 76 mg BA/kg/d, respectively. Mean blood B levels in pregnant rats on gestation day 20 in the pivotal developmental toxicity study were reported to be 1.27 and 1.53 mcg B/g at the NOAEL and LOAEL, respectively. Blood B concentrations in humans are well below these levels. Average blood B levels in the most heavily exposed worker population at a borate mine was 0.24 mcg B/mL, and the estimated daily occupational exposure was equivalent to 160 mg BA/d. Blood B levels in the general population generally range from 0.03 to 0.09 mcg B/mL. These blood B values indicate an ample margin of safety for humans. In summary, the pharmacokinetics of BA in humans and rodents are remarkably similar, and interspecies differences in pharmacokinetics appear to be minimal.

Developmental effects of boric acid in rats related to maternal blood boron concentrations.

Timed-mated Sprague-Dawley rats (60/group) were exposed to boric acid (BA) from gestational days (gd) 0 to 20. BA added to the diet (0, 0.025, 0.050, 0.075, 0.1, or 0.2%) yielded boron (B) intakes of <0.35 (control), 3, 6, 10, 13, or 25 mg B/kg body wt/d. Approximately one-half of the dams/group were terminated on gd 20, maternal whole blood collected and frozen, and prenatal outcome (fetal growth, viability, and morphology) evaluated. Remaining dams received control diet beginning on gd 20, and litters were monitored throughout lactation. Blood samples were prepared by a high-temperature alkaline ashing method and analyzed for B by inductively coupled plasma (ICP) optical emission spectrometry. On gd 20, blood B concentrations of 1.27 +/- 0.298 and 1.53 +/- 0.546 microg B/g were associated with the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) (10 and 13 mg B/kg/d, respectively) for developmental toxicity. Developmental toxicity persisted postnatally only at 25 mg B/kg/d, a dose associated with >10-fold increase in maternal blood B (2.82 +/- 0.987 vs. 0.229 +/- 0.143 microg B/g for controls). Maternal blood B concentrations were: 1. Significantly elevated in all BA-exposed groups. 2. Positively correlated with maternal BA intake. 3. Inversely correlated with fetal body weight at doses above the NOAEL.

Blood boron concentrations in pregnant rats fed boric acid throughout gestation.

Timed-mated Sprague-Dawley rats (28 to 32/group) were exposed to boric acid (BA) in the diet from Gestational Day (GD) 0 to 20. Dietary concentrations of added BA (0%, 0.025%, 0.050%, 0.075%, 0.100%, or 0.200%) yielded average daily intakes equivalent to 0, 3, 6, 10, 13, or 25 mg boron/kg body weight/d. Dams and their fetuses were evaluated for evidence of maternal or developmental toxicity, as reported previously. At termination on GD 20, maternal whole blood was collected in heparinized Vacutainer tubes, stored frozen (-20 degrees C), and subsequently prepared by a high-temperature alkaline ashing procedure for analysis of boron by inductively coupled plasma optical emission spectrometry. Increasing dietary concentrations of BA were positively associated with whole blood boron concentrations in confirmed pregnant rats, specifically 0.229 +/- 0.143, 0.564 +/- 0.211, 0.975 +/- 0.261, 1.27 +/- 0.298, 1.53 +/- 0.546, or 2.82 +/- 0.987 micrograms boron/g whole blood (mean +/- SD) for the control through high-dose groups. Maternal blood boron concentrations were positively correlated with indices of maternal dietary intake of boron and with embryo/fetal toxicity observed at 0.100% and 0.200% BA in the diet reported previously. Thus, blood boron concentrations of 1.27 +/- 0.298 and 1.53 +/- 0.546 micrograms boron/g were associated with the no-observed-adverse-effect level (10 mg boron/kg/d) and lowest-observed-adverse-effect level (13 mg boron/kg/d) for developmental toxicity reported previously.

Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation.

Boric acid (BA), an essential plant micronutrient, occurs naturally in fruits, vegetables, and other foods. It is widely used in the manufacture of glass, ceramics, and other products. In a prior study, gestational exposure to BA was associated with developmental toxicity in the rat, including fetal growth retardation and altered skeletal morphology. In order to establish the developmental toxicity no-observed-adverse-effect level (NOAEL) in the rat, BA (0, 0.025, 0.05, 0.075, 0.1, or 0.2% in feed) was administered to timed-mated rats (60/group) from gestational day (gd) 0 to gd 20. Approximately half the dams were terminated on gd 20, and the remaining dams delivered their litters. Pup growth and viability were monitored until postnatal day (pnd) 21. Dams sacrificed on gd 20 (pnd 21) ingested average doses of 0(0), 19(19), 36(37), 55(56), 76(74), or 143(145) mg BA/kg/day. Maternal clinical signs, body weight, and food and water intake were measured at regular intervals during gestation and lactation. At termination, maternal liver and right kidney were weighed, and live fetuses (gd 20) and pups (pnd 21) were weighed, sexed, and examined for morphological anomalies (external, visceral, skeletal). Maternal effects were limited to increased relative kidney weight at 0.2% BA. Viability of the offspring was unaffected. On gd 20, fetal body weight was 94 and 88% of controls at 0.1 and 0.2% BA, but recovery was complete at birth (approximately gd 22). The incidence of short rib XIII was increased on gd 20 at > or = 0.1% BA, but only at 0.2% on pnd 21. The incidence of wavy rib was increased on gd 20 at > or = 0.1% BA, but the reversibility of this effect was confirmed on pnd 21. A slight decrease in extra lumbar ribs was observed at 0.2% BA on gd 20, and extra lumbar ribs were not found in any pups on pnd 21. Thus, the developmental toxicity NOAEL in the rat was 0.075% BA (55 mg/kg/day) on gd 20 and 0.1% BA (74 mg/kg/day) on pnd 21.

A human health risk assessment of boron (boric acid and borax) in drinking water.

A human health risk assessment was conducted to derive an appropriate safe exposure level in drinking water of inorganic boron-containing compounds (boric acid and borax). Several regulatory agencies have set or plan to set drinking water guidelines or standards for boron (B). Recent publication of reproductive and developmental toxicity studies by the National Toxicology Program prompted this risk assessment, along with the understanding that boron may be nutritionally essential. A rat developmental toxicity study with a NOAEL of 9.6 mg B/kg/day was selected as the pivotal study on which to base this risk assessment, since it represents the most sensitive endpoint of toxicity. A detailed evaluation of these and other studies allowed modifications of the default values for uncertainty factors to account for the pharmacokinetic similarities among species, the lack of metabolism of inorganic boron-containing compounds, the similarity of the toxicity profile across species, the quality of the toxicological database, and other factors according to the approach described by Renwick previously. Benchmark dose calculations were performed, and the results were in close agreement with the NOAEL selected for this risk assessment. The Reference Dose was calculated to be 0.3 mg B/kg/day, resulting in an acceptable daily intake of 18 mg B/day. Considering that the U.S. average dietary intake of boron is 1.5 mg B/day, 16.5 mg B/day could be available for drinking water or other exposures, if any. A preliminary review of boron data in the National Inorganic Radionuclide Survey by the EPA indicates the median boron level in U.S. drinking water supplies to be 0.031 mg B/liter, and most exposures are less than 2.44 mg B/liter (99th percentile). It is concluded that boron in U.S. drinking water would not be expected to pose any health risk to the public.

Pharmacokinetics of [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: analysis with a physiological modeling approach.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hepatic microsomal enzymes. The influence of an inducing dose of TCDD on tissue distribution and other pharmacokinetic behavior of a TCDD analog in the mice was examined by employing a high specific activity radioligand. [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD). Female C57BL/6J mice were pretreated with 0.1 mumol/kg of TCDD or the vehicle only, followed by 0.1 nmol ITCDD/kg 3 days later. The control animals had the highest concentration of ITCDD-derived radioactivity in the fat, but the TCDD-pretreated animals had the highest concentration in their livers. Whole-body elimination of ITCDD approximated first-order behavior, and induction by pretreatment with the inducing dose of TCDD almost doubled the rate of excretion (control mice, t1/2 = 14.2 days; pretreated mice, t1/2 = 8.0 days). All disposition results in naive and pretreated mice were satisfactorily described by a consistent physiologically based pharmacokinetic model (Leung et al., 1988a) in which induction increased the amount of microsomal ITCDD-binding protein from 1.75 to 20 nmol/liver and increased the rate constant for metabolism of free ITCDD from 1 to 3/hr/kg liver. The binding affinity of the microsomal ITCDD-binding protein was the same (20 nM) in both induced and noninduced mice. Model simulations indicated a time delay in the elimination of nonparent ITCDD metabolites from the body and a more rapid absorption of the parent ligand in the pretreated mice. Consistent with previous physiological modeling with TCDD in different mouse strains, the primary factor influencing the liver/fat concentration ratio appears to be the affinity and capacity of the microsomal TCDD-binding proteins, which are altered by induction. These dose-dependent pharmacokinetic differences with ITCDD are important considerations for TCDD risk assessment in which data from high dose rodent experiments are extrapolated to predict behavior at much lower environmental concentrations in exposed humans.

A physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.

A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Sprague-Dawley rat. This description included blood, liver, fat, muscle/skin, and visceral tissue groups. On the basis of other literature, the liver compartment was modeled to include two TCDD-binding sites, corresponding to a cytosolic receptor and a microsomal binding protein. A pharmacodynamic description was developed in which microsomal enzyme induction, both of arylhydrocarbon hydroxylase activity and of the amount of the microsomal TCDD-binding protein, was linked to fractional occupancy of the cytosolic receptor. This description was then used to analyze previously published data on TCDD disposition. The dissociation constant of the cytosolic Ah receptor (KB1) in vivo was estimated to be 15 pM by fitting enzyme induction data from McConnell et al. (1984). The ratio of liver to fat concentration of TCDD (about 4:1) was found to be primarily determined by the dissociation constant of the microsomal binding protein (7 nM) and the basal and induced concentration of this protein in the liver (25 and 200 nmol/liver, respectively). With these parameter values, the tissue distribution of TCDD in fat and liver, the two primary sites of accumulation, was accurately described following either single or repeated dosing with TCDD in the rat. The pharmacokinetic behavior described by the model was extremely sensitive to binding affinities, and only moderately sensitive to binding capacities in the dose range studied. Induction of microsomal TCDD-binding proteins was necessary in order to account for the differences in disposition at low (0.01 microgram/kg) and high (1.0 microgram/kg) daily doses of TCDD. Since the tumorigenicity of TCDD in rats is believed to be correlated with the biological responses of the Ah-TCDD complex, the present physiological pharmacokinetic description, which contains information on receptor occupancy at various dose levels, provides a plausible mechanistic connection for devising pharmacodynamic models which predict the cancer risk of TCDD in the rat.

A proposed occupational exposure limit for 2,3,7,8-tetrachlorodibenzo-p-dioxin.

One contaminant produced unintentionally during the manufacture of chlorophenols and phenoxy herbicides is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The resulting TCDD-containing wastes have been detected at many hazardous waste sites which in recent years have been in the process of remediation. Concerns about worker exposure to TCDD-contaminated soil (dust) during remediation of hazardous waste sites have produced a need for an occupational exposure limit (OEL) for TCDD. The animal toxicology data and human experience with TCDD are reviewed, and an occupational exposure limit for TCDD is proposed. The animal data support risk estimations which are based on TCDD as a nongenotoxic carcinogen. Studies on human populations have failed to demonstrate clearly any significant long-term health effects at levels to which humans have been exposed. The data indicate that an 8-hr time-weighted average limit of 2 ng/m3 is appropriate, and the associated risk would be consistent with other carcinogens at their corresponding OELs. A preliminary OEL of 0.2 ng/m3 (200 pg/m3) is recommended, however, in light of other sources of exposure because of TCDD's ubiquitousness in the environment, its unclear mechanism of action, and its rather long biological half-life in humans. This limit provides an ample margin of safety to prevent chloracne following repeated, acute exposure, and it addresses those chronic effects of TCDD observed in animal studies as well as those observed after accidental human exposure. The resulting body burden caused by chronic exposure to TCDD at the proposed OEL is examined. Its toxicological significance is compared with human tissue data and with other similarly persistent chemicals.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of soil-bound TCDD: oral bioavailability in the rat.

The implications to the public health of trace amounts of 2,3,7,8-TCDD in the environment are under evaluation by regulatory agencies in the United States and Western Europe. One major consideration in such evaluations is the contribution to human exposure via ingestion of TCDD-contaminated soil. An 80% figure is under consideration by some regulators for estimated human exposure. A contractor for one agency has, in fact, used a value of 100% bioavailability for estimating human bioavailability. Several studies have investigated the oral bioavailability of TCDD from contaminated soil in animals. Most have reported estimates of 25-50%, although one has reported less than 0.5 and 85%, depending on the source of the contaminated soil. This paper reports an oral bioavailability of approximately 43% in the rat dosed with three environmentally contaminated soil samples from Times Beach, Missouri. This figure did not change significantly over a 500-fold dose range of 2 to 1450 ng TCDD/kg of body weight for soil contaminated with approximately 2, 30, or 600 ppb of TCDD. The relevance of animal oral bioavailability data for the human remains to be evaluated. However, since regulatory agencies use animal data for extrapolating to humans, the 43% or 25-50% figure would be more accurate than the 80 or 100% estimates.