The effect of dose on the disposition of lead in rats after intravenous and oral administration

Single doses of lead acetate were administered to 250- to 350-g rats by both iv (0.5–15 mg Pb/kg) and po (1–100 mg Pb/kg) routes, and blood lead concentrations were measured up to 25 days following dosing. The area under the blood lead concentration vs time curve (AUC) after iv dosing increased in proportion to increases in the dose. Total blood lead clearance and renal lead clearance were not related to the magnitude of the injected dose.After oral dosing, blood lead concentrations (and AUC) did not increase proportionately with dose. After a 1 mg/kg po lead dose, the extent of absorption was estimated at 42%; this decreased to 2% when the dose was increased to 100 mg/kg. Lead concentrations in the blood, kidneys, liver, and brain of both adult and suckling rats recovered 24 hr after various single po doses also indicated that the extent of lead absorption decreased substantially with increasing dose. Blood and kidney lead concentrations in adult rats exposed for 14 days to lead via drinking water also were not proportional to the apparent amount of lead ingested. The results are consistent with published in vitro data which suggested that the mechanism for gastrointestinal absorption of lead is largely capacity-limited in adolescent and adult rats. Because blood lead concentrations were not a linear function of the oral dose in the rat, the relationship between oral dose and toxic effects of lead may not be a simple one. This factor should be considered when safe lead exposure levels in man are to be established via extrapolation of data from high levels of exposure.     

Relative Bioavailability of Lead from Mining Waste Soil in Rats

The purposes of this study were to determine the extent of absorptionof lead (Pb) in mining waste soil from Butte, Montana, and toinvestigate the effect of mining waste soil dose (g soil/day)on tissue lead concentrations. Young, 7- to 8-week-old maleand female Sprague-Dawley rats (5/sex/group) were given miningwaste soil that contained 810 or 3908 ppm lead mixed in a purifieddiet (AIN-76) at four different dose levels (0.2, 0.5, 2, and5% dietary soil) for 30 consecutive days. Standard groups includeduntreated controls and dosed feed soluble lead acetate groups(1, 10, 25, 100, and 250 µg Pb/g feed). The test soildose levels bracketed a pica child's soil exposure level andthe lead acetate concentrations bracketed the test soil doselevels of lead. Liver, blood, and femur were analyzed for totallead concentration using graphite furnace atomic absorptionspectroscopy. Clinical signs, body weight, food consumption,and liver weights for test soil and standard groups were similarto control. Tissue lead concentrations from test soil animalswere significantly lower than the tissue concentrations forthe lead acetate group. Relative percentage bioavailabilityvalues, based on lead acetate as the standard, were independentof the two different test soils, dose levels, and sex and wereonly slightly dependent on the tissue (blood> bone, liver).Mean relative percentage bioavailability values of lead in theButte mining waste soil were 20% based on the blood data. 9%based on the bone data, and 8% based on the liver data. Theresults of this study will provide the information needed todetermine the significance of lead exposure from Butte soilsin assessing human health risks as part of the Superfund RemedialInvestigation/Feasibility Study process.     

Subchronic lead feeding study in male rats and micropigs

This study compared the lead uptake from contaminated test soil of known lead concentration with a soluble lead acetate standard, which was considered to be 100% bioavailable. This study also compared the lead bioavailability from this lead-contaminated soil between rats and micropigs. Harlan Sprague-Dawley rats and Yucatan micropigs were fed lead-contaminated soil as a 5% (w/w) mixture with their diet. The lead-contaminated soil was either a specific test soil of known lead concentration (1000 microg/g) or basal low concentration lead soil ( approximately 135 microg/g), which was spiked with lead acetate to match the lead content of the test soil. The effective diet lead concentration was 50 microg Pb/g diet. Results demonstrated that rats reached steady-state concentrations of blood lead by week 2, whereas micropigs did not reach steady state until week 4. In addition, final blood lead concentrations in micropigs were four-fold higher than those in rats. In the micropigs, the final blood lead levels in the test soil study group were significantly lower than those in the lead acetate study group, although there was no significant difference between study groups in the rats. Tissue lead concentrations were significantly higher in micropigs than those in the rats, although the diet lead concentrations in both sets of animals were the same. In summary, because of the greater sensitivity in demonstrating higher tissue lead incorporation in micropigs as compared to rats, the micropig is a better animal model for demonstrating the differences in relative lead bioavailability when testing different sources of lead-contaminated soils.     

Comparative Absorption of Lead from Contaminated Soil and Lead Salts by Weanling Fischer 344 Rats

A 44-day dosed feed study was performed to compare the bioavailabilityof lead from contaminated soil versus two lead salts and theeffect of soil on gastrointestinal absorption of ingested lead.Male Fischer rats (approximately 4 weeks of age) received lead,17, 42, or 127 ppm, in the form of lead acetate, lead sulfide,lead-contaminated soil, or combinations thereof in the dietfor 7, 15, or 44 days. Control soil was added to the diets ofsome animals to determine how it might alter lead bioavailability.Blood -aminolevulinic acid dehydratase (-ALAD) and blood, bone,kidney, and liver lead were determined in groups of animalsat each time-point. Blood -ALAD was inhibited in a dose-dependentmanner and to the greatest degree in the lead acetate and leadacetate/control soil groups, followed by the lead sulfide andleadcontaminated soil groups. Bone and tissue lead levels increasedin a dose-dependent manner and were greatest in animals receivinglead acetate and significantly less in animals receiving leadsulfide and lead-contaminated soil. Blood lead levels were generallygreatest by 7 days and stabilized at lower levels thereafter.Bone lead concentration—time patterns did not demonstratethe biphasic change seen with tissues and continued to increasein most treatment groups through the course of the study. Thepresence of soil in the diet clearly attenuated the absorptionof lead acetate, but had little effect on the absorption oflead sulfide. Results of these studies confirm previous observationsthat lead absorption is highly dependent on the form of leadingested and the matrix in which it is ingested. More important,these studies demonstrate that lead in soil may be significantlyless available than estimated by current default assumptionsand that the presence of soil may decrease the availabilityof lead from lead salts on which the default assumptions arebased. Results presented here also demonstrate that the weanlingrat may represent an appropriate model that could be used toobtain relatively rapid and economical estimates of the availabilityof lead in complex matrices such as soil.     

Effect of Diet on Blood Lead Concentration in the Cynomolgus Monkey

Effect of Diet on Blood Lead Concentration in the CynomolgusMonkey. TRUELOVE, J. F., GILBERT, S. G., AND RICE, D. C. (1985).Fundam. Appl. Toxicol. 5, 588–596. Infant cynomolgus monkeys(Macaca fascicularis) were reared from birth in an infant primatenursery and dosed with lead acetate (2 mg Pb/kg body wt/day)from approximately 100 days of age. The monkeys were switchedfrom an infant formula diet to a diet of primate chow and waterat 460 days of age. Beginning at approximately 935 days of age,various diets were fed in the following order infant formulaplus a restricted amount of primate chow, infant formula only,infant formula plus cellulose fiber, infant formula plus phyticacid, cow's milk, and primate chow plus water. Blood lead contentwas determined throughout the experiment. At 360 days of treatment(approx. 460 days of age) the blood lead concentration was 90µg/dl but decreased to 50 µg/dl within 30 days afterthe diet was changed to primate chow and water. When the monkeyswere 935 days of age the introduction of the infant formulaplus a restricted amount of primate chow had little effect onblood lead concentrations. However, when primate chow was removedfrom the diet so that the monkeys were fed infant formula only,there was a rapid increase in blood lead from approximately40 to 220 µg/dl. The addition of cellulose fiber to theinfant formula had no effect on blood lead concentrations, whereasthe addition of phytic acid caused an abrupt decrease to approximately85 µg/dl. Blood lead concentrations increased to approximately190 µg/dl when cow's milk only was fed and decreased toapproximately 55 µg/dl when the monkeys were returnedto a diet of primate chow and water. In a second experiment,infant monkeys were reared as above and dosed from birth withlead acetate at a rate of 25 µg Pb/kg body wt/day. Themonkeys were switched to a primate chow and water diet at 200days of age and at approximately 900 days of age various dietarychanges were made that were similar to those described above.Although blood lead concentrations were much lower and moreviable than in the 2-mg/kg/day dose group, the data showed apattern similar to those of the higher dose group     

Ascorbic acid supplementation does not improve efficacy of meso-dimercaptosuccinic acid treatment in lead-exposed suckling rats

It was suggested that ascorbic acid as a natural chelating agent can influence lead toxicokinetics and improve chelating properties of dimercaptosuccinic acid (DMSA) in adult rats. In this paper potential benefits of ascorbic acid supplementation, alone or combined with DMSA, in decreasing lead retention in suckling rats were evaluated. Such data in young mammals are not available. L-Ascorbic acid (daily dose 650 mg/kg b.wt.) and/or DMSA (daily dose 91 mg/kg b.wt.) were administered orally to suckling Wistar rats either during ongoing 8-day oral lead exposure (as acetate; daily dose 2 mg lead/kg b.wt.) or after 3-day lead exposure (total dose 12 mg lead/kg b.wt.). Lead concentrations were analysed in the carcass (skeleton), liver, kidneys and brain by atomic absorption spectrometry. By ascorbic acid supplementation lead retention was not reduced under either lead exposure condition. Lead concentration was even increased in the carcass. Treatment with DMSA under both exposure conditions significantly reduced lead in all analysed tissues. Combined treatment with ascorbic acid and DMSA during ongoing lead exposure was substantially less effective than DMSA treatment alone, and did not affect DMSA efficacy when administered after lead exposure. It was concluded that ascorbic acid administered either during or after lead exposure in suckling rats has no beneficial effect on either lead retention or DMSA chelation effectiveness.     

Minimal Behavioral Effects from Moderate Postnatal Lead Treatment in Rats

Developmental lead exposure continues to be a worldwide problem. This study investigated the behavioral effects resulting from developmental lead treatment in rats with corresponding physiological measures of lead exposure. Sprague–Dawley rats were treated with 350 ppm lead acetate from birth to weaning via the dam’s drinking water. Behavioral measures assessed in the offspring included residential activity tests, complex maze performance, acoustic startle response, emergence behavior (light/dark preference), prepulse inhibition, and ethological assessments of play, dominance, and burrowing. Pb blood levels averaged 53 μg/dl in the dam at the time of offspring weaning and 46 μg/dl in weanling female offspring. Pb levels averaged 277 ng/g and 32 μg/g in the brain and bone, respectively, of female offspring at weaning. No behavioral assessment indicated any lead-related functional alterations nor were there any statistically significant differences when the lead-treated group was restricted to rats in those litters that were above the median Pb blood lead level at weaning. These results indicate that any lead-related functional alterations at this dose may be subtle and require a sufficient demand on the system for detection.     

Lead, zinc, and copper levels in intraocular brain tissue grafts, brain, and blood of lead-exposed rats

Adult female Sprague-Dawley rats were exposed to various concentrations of lead acetate for different lengths of time. Six weeks exposure to lead acetate at concentrations of 0, 0.125, 0.25, 0.5, 1, and 2% in the drinking water, gave rise to brain and blood lead levels that were highly correlated with the lead concentration in the drinking water. When animals were exposed to 1% lead acetate for different lengths of time, an apparent delay in the rate of lead transport into the brain was seen during the first day. However, if animals were exposed for longer time periods, brain lead levels increased faster than did the blood levels. Pieces of fetal cortex cerebri were grafted to the anterior eye chamber of host animals exposed to either 1% lead acetate or to sodium acetate. Six weeks after grafting, the lead concentration in the lead-exposed grafts were 31.6 mg/kg dry wt, as compared to 6.4 mg/kg dry wt in sodium acetate control grafts. However, grafts from both groups had lead levels that were approximately five times higher than in cerebral cortex “punches” from corresponding areas of the host brains. Furthermore, zinc and copper levels were also higher in the grafts as compared to punches of in situ cortex. Taken together with previous reports on animal and human lead exposure, these data indicate that oral lead intake in adult rats bearing intraocular brain grafts yields blood and brain levels which are physiologically relevant to problems of clinical lead toxicity.     

Lead in blood and brain regions of rats chronically exposed to low doses of the metal

The concentration of lead in blood and cerebral cortex (Cx), striatum (St), hippocampus (Hc), and midbrain (Mb) was measured by flameless atomic absorption spectrophotometry in rats that had received (po) daily 0.005, 0.025, 0.1, or 1.0 mg lead/kg from 3 days until 4, 6, or 8 weeks of age. The blood lead levels and regional brain lead content of control rats increased with age. In addition to a dose-dependent increase in blood lead levels of rats exposed to 0.1 mg lead/kg (by 176%) and 1.0 mg lead/kg (by 396%), the concentration of the metal in blood of rats treated with the 0.1 mg/kg dose initially increased with the duration of exposure, reached a maximum value of 13.8 μg/dl at 6 weeks of age, and leveled off thereafter. Whereas exposure to small amounts of lead (0.025 mg/kg) resulted in a preferential accumulation of lead in the Hc (by 127%), a larger dose of the metal (0.1 mg/kg) administered for the same period of time produced significant increases in the lead content of the Cx (by 80%), St (by 106%), Hc (by 134%), and Mb (by 67%); no significant interregional differences in lead content were noted. The duration of treatment also influenced the distribution of lead. Exposure to 0.1 mg lead/kg for 4 weeks resulted in a significant increase in the lead levels of only the Cx (by 125%) and Hc (by 522%), while the same treatment for 8 weeks resulted in a significant and similar accumulation of lead in all of the regions examined. These data indicate that in the case of chronic low-level lead poisoning, brain regional lead distribution is influenced by both the dose of the metal administered and the duration of exposure. Significant amounts of lead persisted in brain tissue for as long as 2 and 4 weeks after the withdrawal of lead treatment.     

Calcium Supplementation Efficiently Reduces Lead Absorption in Suckling Rats*

Abstract: The effect of calcium supplementation on tissue lead was evaluated in suckling Wistar rats. Such data are not yet available in the literature. The following artificial feeding regimen was used for calcium supplementation: cow's milk by addition of 1%, 3% or 6% Ca as CaHPO₄×2H₂O suspension to increase the daily calcium intake about 1.4, 2 or 3 times above control values. Artificial feeding was applied during 7 hr each day for nine consecutive days (from day 6 through 15 after birth). The effect of such treatment on lead absorption and elimination was evaluated in two separate experiments: calcium supplementation during oral lead exposure (as acetate; daily dose 2 mg Pb/kg body wt.; total Pb dose 18 mg/kg body wt.) or after a single intraperitoneal lead administration (5 mg/kg body wt.). At the end of experiments, lead in tissues (liver, kidneys, brain and carcass), and essential elements (Ca, Fe, Zn, Cu) were analysed by atomic absorption spectrometry. Calcium supplementation caused a statistically significant decrease of lead in all tissues of sucklings orally exposed to lead. This decrease was dose‐related being about 1.3, 1.5 and 2 times lower in groups supplemented with 1%, 3%, or 6% calcium compared to controls, respectively. Increased calcium intake had no effect on incorporated lead after parenteral lead exposure. Calcium supplementation increased carcass calcium and had no effect on trace elements in tissues, pups' general appearance and body weight gain. It is concluded that higher calcium intake might be a way of efficient reduction of lead absorption during the suckling period.     

Effects of 1,25-dihydroxicolecalciferol and dietary calcium-phosphate on distribution of lead to tissues during growth

The susceptibility to the toxic effects of lead (Pb) is mainly mediated by age and nutritional and hormonal status, and children are among the most vulnerable to them. During growth, an increase in calcium, phosphate and vitamin D in diet is recommended to enhance calcium and phosphate intestinal absorption and bone deposit. Calcium and phosphate reduce lead intestinal absorption, and 1,25-dihydroxicolecalciferol (1,25(OH)2D3) (active metabolite of vitamin D) increases both lead and calcium intestinal absorption. However, the effects of 1,25(OH)2D3 on lead bone deposit and redistribution to soft tissues are not well known. In this study, we examined the effects of calcium-phosphate diet supplementation and the administration of 1,25(OH)2D3 on Pb distribution to soft tissue and bone in growing rats exposed to Pb. Rats (21 days old) were exposed for 28 days to 100 ppm of Pb solution in drinking water. Calcium and phosphate in diet were increased from 1 to 2.5% and from 0.65 to 1.8%, respectively, and 1,25(OH)2D3 was administrated by intraperitoneal injection of 7.2 ng/kg every 7 days. Between 21 and 49 days, the body weight increased about 5 times. The results showed that high calcium-phosphate diet led to lower Pb concentration in blood and in bone, but Pb liver and kidney concentrations increased, which indicates that absorption and bone deposit redistribution of Pb decreased. On the other hand, no effect of this diet rich in calcium-phosphate in Pb concentration was observed in brain. Blood and bone Pb concentrations increased even more when the high calcium-phosphate diet included 1,25(OH)2D3. In the rats treated only with 1,25(OH)2D3, blood and bone Pb concentrations were lower. Higher concentrations of lead in the soft organs were observed also in rats treated under a high calcium-phosphate diet plus 1,25(OH)2D3 administration. The above mentioned results suggested that 1,25(OH)2D3 induces an increased absorption and redistribution of Pb, and therefore, it may enhance systemic damage in Pb-exposed growing animals.     

Effect of Different Levels and Periods of Lead Exposure on Tissue Levels and Excretion of Lead, Zinc, and Calcium in the Rat

Effect of Different Levels and Periods of Lead Exposure on TissueLevels and Excretion of Lead, Zinc, and Calcium in the Rat.Victery, W., MILLER, C. R., ZHU, S.-Y., AND GOYER, R. A. (1987).Fundam. Appl. Toxicol. 8, 506–516. Influence of lead ontissue content and urinary excretion of lead, zinc, and calciumin rats was studied following various exposure periods. Weanlingmale rats were fed a trace mineral-sufficient diet with either0, 200, 500, or 1000 ppm lead (as acetate) in drinking waterfor 4, 8, or 12 weeks. Blood lead ranged from 40 to over 100µg/dl; kidney lead was highest at 4 weeks. Urinary leadexcretion was highest at 4 weeks and declined with longer exposure.Urinary zinc excretion correlated positively with lead excretionat the lower excretion rates but plateaued at higher lead excretionrates. After 12 weeks exposure at each lead dose employed, decreasedzinc concentration was observed in testes, bone, and brain.Plasma, erythrocyte, and kidney zinc were not affected, whilepancreas and liver zinc were slightly elevated. Urine calciumwas increased significantly only in rats exposed to 1000 ppm,possibly reflecting renal cell damage as determined by elevatedrenal calcium levels. These results indicate that lead doseis more important than exposure period for determining kidneylead levels, while urinary lead excretion rate is both doseand time dependent. Blood lead clearance values are relativelyindependent of dose and fall as exposure continues. Essentialtrace metal balance for zinc, especially, and to a lesser extentfor calcium, is affected by the dose and length of chronic leadexposure.     

Lead exposure during advanced age: alterations in kinetics and biochemical effects

The transition from maturity to advanced age is accompanied by a multitude of degenerative processes, several of which could be hypothesized to enhance the vulnerability of animals to the toxic effects of lead (Pb). That premise was examined in this study which evaluated kinetic and biochemical responses of young (21 day old), adult (8 months), and old rats (16 months) exposed to 0, 2, or 10 mg Pb acetate/kg/day for a period of 9.5 months. Results indicated an enhanced vulnerability to Pb in older rats which may be due both to increased Pb exposure as a result of elevated soft tissue target organ levels and to a greater sensitivity to the biochemical effects of Pb. Differences in the tissue distribution of Pb with age included lower bone levels, but increased concentrations in brain, liver, and kidney. These effects did not appear to reflect enhanced Pb uptake from the GI tract with age since differences in blood Pb levels over the course of exposure were not remarkable. Instead, they may be due to changes in bone physiology with age, combined with altered patterns of urinary Pb excretion over time. Biochemical effects of Pb, as manifested by elevation of erythrocyte zinc protoporphyrin and urinary delta-aminolevulinic acid excretion occurred earlier in the course of exposure (3 months) in older rats than in young rats (9.5 months of exposure). Grossly enlarged spleens were noted only in old rats exposed to Pb. These findings raise questions and concerns about the contributions of a lifetime of lead exposure to the deteriorating health conditions associated with old age.     

Bioavailability and metabolism of hydroquinone after intratracheal instillation in male rats.

The purpose of this study was to investigate the rate and extent of hydroquinone (HQ) absorption and first pass metabolism in the lungs of male rats in vivo. [14C]HQ in physiological saline was administered intratracheally via an indwelling endotracheal tube to simulate inhalation exposure to HQ dust. The bioavailability of HQ was determined by blood sampling simultaneously at arterial and venous sites beginning immediately after administration to conscious rats. Pulmonary absorption and metabolism, and systemic metabolism and elimination were determined by chromatographic analysis of parent compound and metabolites in blood samples after intratracheal administration of [14C]HQ at 0.1, 1.0, and 10 mg/kg. Pulmonary absorption of HQ was found to be very rapid with [14C]HQ detectable in arterial blood, and to a lesser extent in venous blood, within 5 to 10 s after dose administration. Only [14C]HQ was detected in the initial (5-10 s) arterial blood samples at all dose levels, indicating that pulmonary metabolism of HQ was not extensive. However, later blood samples (45-720 s) indicated rapid metabolism and elimination of the parent compound and metabolites after intratracheal absorption. The elimination half-life from the 0.1 mg/kg dose was allometrically scaled to human proportions and used to estimate the steady-state (maximum) human blood concentrations of HQ resulting from presupposed workplace exposures. The estimates indicated minimal levels of HQ in human blood after respiratory exposures of greater than 1 h at 0.1 or 2.0 mg/m3; these levels were less than background concentrations of HQ detected in human blood in previous studies.     

Acute Exposure to Low Lead Levels and its Implications on the Activity and Expression of Cytosolic Thioredoxin Reductase in the Kidney

Renal thioredoxin reductase‐1 (TrxR‐1) activity is stimulated at lead doses lower than that necessary to inhibit δ‐aminolevulinate dehydratase activity (δ‐ALA‐D), which is a classical early biomarker of lead effects. Thus, we hypothesized that the activity of TrxR‐1 could be a more sensitive early indicator of lead effects than is δ‐ALA‐D. To evaluate this hypothesis, we assessed the blood and renal TrxR‐1 activity and its gene expression along with biomarkers of oxidative damage, antioxidant enzyme activities and biomarkers of lead exposure in rats acutely exposed to lead. A histopathological analysis was performed to verify renal damage. The increase in renal TrxR‐1 activity paralleled the increase in the blood and renal lead levels at 6, 24 and 48 hr after the exposure to 25 mg/kg lead acetate (p < 0.05), whereas its expression was increased 24 and 48 hr after exposure. These effects were not accompanied by oxidative or tissue damage in the kidneys. Blood TrxR‐1 activity was not affected by lead exposure (up to 25 mg/kg). Erythrocyte δ‐ALA‐D activity was inhibited 6 hr after the exposure to 25 mg/kg lead acetate (p < 0.05) but recovered thereafter. Renal δ‐ALA‐D activity decreased 24 and 48 hr after the exposure to 25 mg/kg lead acetate. There were no changes in any parameters at lead acetate doses <25 mg/kg. Our results indicate that blood TrxR‐1 activity is not a suitable indicator of lead effects. In contrast, the increase in renal TrxR‐1 expression and activity is implicated in the early events of lead exposure, most likely as a protective cellular mechanism against lead toxicity.     

Marginal zinc deficiency exacerbates bone lead accumulation and high dietary zinc attenuates lead accumulation at the expense of bone density in growing rats.

Environmental lead exposure is associated with reduced bone growth and quality, which may predispose to osteoporosis. Zinc supplementation may reduce lead accumulation; however, effects on bone development have not been addressed. Our objective was to investigate the effects of marginal zinc (MZ) and supplemental zinc (SZ) intakes on bone lead deposition and skeletal development in lead-exposed rats. In a factorial design, weanling Sprague-Dawley rats were assigned to MZ (8 mg/kg diet); zinc-adequate control (CT; 30 mg/kg); zinc-adequate, diet-restricted (DR; 30 mg/kg); or SZ (300 mg/kg) groups, with and without lead acetate-containing drinking water (200 mg Pb/l) for 3 weeks. Excised femurs were analyzed for bone mineral density (BMD) by dual-energy x-ray absorptiometry, morphometry, and mineral content. MZ had higher femur lead and lower femur zinc concentrations and impaired skeletal growth and mineralization than CT. DR inhibited growth but did not result in higher femur lead concentrations than CT. SZ had higher femur zinc and lower femur lead concentrations than the other treatments. DR and SZ had impaired BMD versus CT and MZ. Lead also retarded skeletal growth and impaired BMD, but an interaction between lead and MZ was only found for femoral knee width, which was lower in MZ exposed to lead. In summary, while MZ deficiency exacerbated bone lead concentration, it generally did not intensify lead toxicity. SZ was protective against bone lead but was detrimental to BMD, suggesting that the optimal level of SZ to reduce lead absorption, while supporting growth and bone development, requires further investigation.     

Cytotoxicity of food dyes on cultured fetal rat hepatocytes

Single doses of lead (trace to 445 mg/kg) were administered per os to suckling and adult mice. Both groups exhibited dose-independent lead retention when doses of 4 to 445 mg/kg were administered. However, developmental differences in the fraction of initial dose (FID) retained were evident for all doses administered. A much larger FID was retained in both age groups following administration of carrier-free ²⁰³Pb. The results are consistent with a mechanism of gastrointestinal lead absorption comprising two or more proceeses. Developmental differences were also observed in organ lead concentration relative to whole body concentration for kidneys, skull, and brain 6 days following lead administration. Lead retentions (relative to whole body retention) in brain and in bone were linearly related to dose of lead administered in both suckling and adult age groups. Though uptake of lead into brain and into femur was observed to be directly related to dose over a wide range, relative blood lead concentrations were not linearly correlated with dose administered. The relationships between lead concentrations of blood and organ(s) were also shown to be nonlinear relative to dose. However, blood lead concentration was found to be a reliable indicator of kidney and liver lead concentrations following an acute lead exposure.     

Effects of lead on glutathione S-transferase expression in rat kidney: a dose-response study.

Glutathione S-transferases (GST, EC 2.5.1.18) are a family of phase II detoxification enzymes involved in the conjugation of glutathione to a highly diverse group of compounds. The purpose of this study was to evaluate the dose-response effects of lead acetate administration on the expression of rat kidney GST. Sprague-Dawley rats were injected with doses of lead acetate ranging from 0.11 to 114 mg/kg (0.3 to 300 mumol/kg) for three consecutive days and sacrificed 24 h later. Kidney GST activity, GST isoform HPLC profiles, blood lead analysis, and electron microscopy were performed. A dose of 1.1 mg/kg lead acetate resulted in a blood lead level of 26 micrograms/dl and produced a significant increase in GST activity which continued to increase with dose up to 38 mg/kg. Morphological changes were detected at 3.8 mg/kg and increasing severity of cellular damage paralleled dose, blood lead levels, and changes in body weight. Individual GST isoforms exhibited different thresholds and maxima; rGSTP1 and rGSTM1 had thresholds of 1.1 and 3.8 mg/kg, respectively, very similar rates of increase with dose, and a maximum yield that was 450% above control at a dose of 38 mg/kg for both enzymes. rGSTA1 and rGSTA3 showed similar thresholds (1.1 mg/kg) and maximal fold increase (275%) but varied in the relative response to each dose. These results indicate that renal GST increases occur at lead levels which are environmentally significant, that these changes precede cellular damage, and suggest that GST may serve as a tissue biomarker of lead exposure.     

Lead in blood and tissues of mice after administration of low lead doses

Lead levels in whole blood could be determined reliably up to a lower limit of 2 g/100 ml blood, using a modified micromethod of the graphite tube furnace technique. Lead contents of various tissues were also determined by using the automated graphite tube furnace after wet ashing of the organs with nitric acid in autoclaves.Animal experiments with mice showed no measurable increase in blood lead level after a single, 10- or 30-days oral administration of lead in doses of 10–1000 g lead acetate/kg body weight/day. However, these doses led to a rise in tissue lead content. There was a clear dependence of tissue lead content on type of organ examined, lead dose and duration of lead exposure.According to our experiments, the threshold dose which leads to a long-term increase in tissue lead content is assumed to be about 100 g lead acetate/kg body weight/day, orally administered.We are thankful to Prof. Dr. H. Rüssel, Hannover and Dr. M. Fleischer, Saarbrücken for helping in comparison studies.We would also like to thank Mr. H. Dick and Miss. Ch. Hecker for the technical and laboratory assistance.     

Effects of Lead Exposure on Bromocriptine-Induced Penile Erection in Rats

Abstract: In the present work we have studied the effects of lead exposure on penile erection induced by bromocriptine. Intraperitoneal injection of bromocriptine (2, 3, 4 and 8 mg/kg) induced dose-related penile erection in rats. Maximum response was observed with 4 mg/kg of the drug. Lead exposure (as Pb-acetate in drinking water) for periods of 7, 14, 21 and 28 days decreased the bromocriptine-induced penile erection response. Higher concentrations of lead (0.05%) were shown to cause a more prominent decrease of penile erection. The same procedure for lead administration did not significantly alter penile erection induced by physostigmine (0.1 and 0.3 mg/kg, intraperitoneally). In a series of experiments, blood lead concentrations were measured 7 and 21 days after lead exposure. Significant increases of lead concentrations were found after lead exposure. It is concluded that lead can influence bromocriptine-induced penile erection.