Evaluation of factors associated with cadmium exposure and kidney function in the general population

Cadmium (Cd) is a nonessential toxic metal which is widely distributed in the environment. The general population is exposed to low levels of Cd and the kidney is the organ most sensitive to Cd toxicity. This study was performed to simultaneously evaluate Cd exposure, kidney function, and oxidative stress biomarkers in the general population. A total of 643 adults were interviewed to document demographic characteristics, lifestyles, past‐medical history, and diet during the last 24 h. We estimated daily Cd intake based on the diet of study subjects who had not been exposed to Cd occupationally. Whole blood and urine samples were collected and analyzed to determine Cd concentrations and kidney function indices (β₂‐microglobulin [β₂‐MG], N‐acetyl‐β‐D ‐glucosaminidase [NAG], metallothionein [MT]). The oxidative stress index (malondialdehyde [MDA]) was determined from the urine. The daily Cd intake from diet was established as 7.07 μg/day. The mean concentration of Cd measured in the blood was 1.22 μg/L and urine was 0.95 μg/g creatinine. The concentrations of Cd in blood and urine were higher in females than in males. The blood levels of Cd were affected by sex, age, and smoking, and urine Cd was influenced by sex, age, and blood Cd. The urine Cd was positively correlated with MT, NAG activity, and MDA in females, but with NAG only in males. The blood Cd was associated with MT in males. Increased NAG activity was observed when Cd in urine reached 1.0 μg Cd/g creatinine and was also affected by age, hypertension, and diabetes mellitus. Urinary MT only responded to Cd in urine or blood. In summary, exposure to Cd in the general population was influenced by various factors including sex, age, and smoking habits. Such exposure might eventually cause tubular damage in the kidneys through the oxidative stress mechanism, and females might be more susceptible than males to Cd exposure under the environment. © 2011 Wiley Periodicals, Inc. Environ Toxicol 28: 563–570, 2013.     

Pharmacokinetics/pharmacodynamics (PK/PD) modeling of risks of kidney toxicity from exposure to cadmium: estimates of dietary risks in the U.S. population

An analysis of epidemiological studies of associations between exposure to cadmium and kidney toxicity was conducted. Dose-response functions relating low-molecular-weight (LMW) proteinuria to various indices of cadmium dose (dietary cadmium intake, urinary cadmium excretion, or tissue cadmium burden) were obtained from 15 studies of diverse exposures (occupational, general environmental, environmental contamination). Estimates of the dose corresponding to probabilities of LMW proteinuria of 0.1, 0.15, or 0.2 were transformed from the reported dose units into corresponding estimates of target organ dose (microgram Cd/g renal cortex, RC) by simulation using a pharmacokinetics (PK) model. The median RC associated with a 0.1 probability (RC10M) of LMW proteinuria was predicted to be 153 micrograms Cd/g cortex (95% confidence interval [CI]: 84-263). The lower confidence limit on the RC10M (RC10L, 84 micrograms/g cortex) was predicted to be attained with a constant chronic intake of 1 microgram/kg/d in females or 2.2 micrograms/kg/d in males. The RC10L was 2.5-5 times higher than the median RCs predicted to result from dietary cadmium intake in U.S. nonsmokers (microgram Cd/g cortex: 33, females; 17, males) and 1.6-3 times higher than the corresponding 95th percentile RCs (53, females; 27, males). Additional exposure from smoking cigarettes (approximately 20 cigarettes/d, 3 micrograms Cd inhaled/d) was predicted to increase the median RC (microgram/g cortex) by approximately 45-70% (48, females; 29, males); however, predicted 95th percentile RCs for smokers (66, females; 38, males) were lower than the RC10L. These results indicate that, for most of the U.S. population, dietary-derived risks are likely to be negligible, in the absence of exposures from other sources.     

Arsenic speciation in the urine and hair of individuals exposed to airborne arsenic through coal-burning in Guizhou,PR China

The extent of exposure of residents of Changqing (Guizhou, PR China) to arsenic through coal-burning was investigated. Despite the low coal-arsenic content (56.3+/-42.5 mg As kg(-1)) when compared with coals collected at different location and times from the same province, more than 30% of the study subjects have shown symptoms of arsenicosis. Coal, urine, hair, and water samples were collected in mid-September 2001 and analysed for arsenic. The average urinary and hair-arsenic concentrations in the exposed subjects were 71.4+/-37.1 microg As g(-1) creatinine (control 41.6+/-12.1) and 7.99+/-8.16 mg kg(-1), respectively. A positive correlation between the hair and urinary-arsenic concentration (R(2)=0.601) was found. There was no significant difference between females and males for both urinary and hair-arsenic concentrations. Females were found to have a higher dimethylarsinic acid but lower percentages of inorganic arsenic and monomethylarsonic acid in their urine than males.     

Concentrations of arsenic,cadmium and lead in human hair and typical foods in eleven Chinese cities

Concentrations of arsenic (As), cadmium (Cd) and lead (Pb) were determined in 384 human hair samples and 445 purchased food samples from 11 cities in China. The mean concentrations of hair As, Cd and Pb were 0.23, 0.062 and 2.45 mg kg⁻¹, respectively. The As, Cd and Pb concentrations in different foods were lower than the national maximum allowable contaminant levels. By comparison, males had higher hair As concentrations but lower Cd concentrations than females. When the interaction effects of gender and age were considered, males had the higher hair As, Cd and Pb concentrations in the 51–65 year-old age group. Residents of rural areas had higher hair As, Cd and Pb concentrations than people living in urban areas. Further analysis indicates that hair As, Cd and Pb concentrations and their changes with biological and environmental factors cannot be satisfactorily explained by the estimated intakes from purchased food.     

Metabolism and tissue distribution of orally administered trichloroethylene in male and female rats: identification of glutathione- and cytochrome P-450-derived metabolites in liver, kidney, blood, and urine

Male and female Fischer 344 rats were administered trichloroethylene (TRI) (2, 5, or 15 mmol/kg body weight) in corn oil by oral gavage, and TRI and its metabolites were measured at times up to 48 h in liver, kidneys, blood, and urine. Studies tested the hypothesis that gender-dependent differences in distribution and metabolism of TRI could help explain differences in toxicity. Higher levels of TRI were generally observed in tissues of males at lower doses. Complex patterns of TRI concentration, sometimes with multiple peaks, were observed in liver, kidneys, and blood of both males and females, consistent with enterohepatic recirculation. Higher concentrations of cytochrome P-450 (P450)-derived metabolites were observed in livers of males than in females, whereas the opposite pattern was observed in kidneys. Trichloroacetate was the primary P450-derived metabolite in blood and urine, although it generally appeared at later times than chloral hydrate. Trichloroethanol was also a significant metabolite in urine. S-(1,2-Dichlorovinyl)glutathione (DCVG) was recovered in liver and kidneys of female rats only and in blood of both males and females, with generally higher amounts found in females. S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), the penultimate nephrotoxic metabolite, was recovered in male and female liver, female kidneys, male blood, and in urine of both males and females. The relationship between gender-dependent differences in distribution and metabolism of TRI and susceptibility to TRI-induced toxicity is discussed.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

Genetic polymorphisms in AS3MT and arsenic metabolism in residents of the Red River Delta, Vietnam

To elucidate the role of genetic factors in arsenic (As) metabolism, we studied associations of single nucleotide polymorphisms (SNPs) in As (+ 3 oxidation state) methyltransferase (AS3MT) with the As concentrations in hair and urine, and urinary As profile in residents in the Red River Delta, Vietnam. Concentrations of total As in groundwater were 0.7-502 μg/l. Total As levels in groundwater drastically decreased by using sand filter, indicating that the filter could be effective to remove As from raw groundwater. Concentrations of inorganic As (IAs) in urine and total As in hair of males were higher than those of females. A significant positive correlation between monomethylarsonic acid (MMA)/IAs and age in females indicates that older females have higher methylation capacity from IAs to MMA. Body mass index negatively correlated with urinary As concentrations in males. Homozygote for SNPs 4602AA, 35991GG, and 37853GG, which showed strong linkage disequilibrium (LD), had higher percentage (%) of dimethylarsinic acid (DMA) in urine. SNPs 4740 and 12590 had strong LD and associated with urinary %DMA. Although SNPs 6144, 12390, 14215, and 35587 comprised LD cluster, homozygotes in SNPs 12390GG and 35587CC had lower DMA/MMA in urine, suggesting low methylation capacity from MMA to DMA in homo types for these SNPs. SNPs 5913 and 8973 correlated with %MMA and %DMA, respectively. Heterozygote for SNP 14458TC had higher MMA/IAs in urine than TT homozygote, indicating that the heterozygote may have stronger methylation ability of IAs. To our knowledge, this is the first study on the association of genetic factors with As metabolism in Vietnamese.     

Impact of consumption of freshwater fish on mercury levels in hair, blood, urine, and alveolar air

Human exposure to methylmercury occurs mainly via consumption of fish. The aim of the study was to investigate the influence of freshwater fish consumption on mercury levels in hair, blood, urine, and end-exhaled air. Twenty subjects without dental amalgam fillings were recruited from sport-fishing societies. They ranged in age from 61 to 87 yr. Six individuals ate freshwater fish at least once a week and were categorized as high consumers. Eight individuals were classified as medium consumers and ate freshwater fish at least once a month but less than once a week. Six individuals were categorized as low consumers and had not eaten freshwater fish in the past 3 mo. Among the high consumers, median concentrations of mercury were 8.6 microg/L in blood, 2.4 microg/g in hair, 10 pg/L in end-exhaled air, and 1.1 microg/g creatinine in urine. The relationship between freshwater fish consumption and mercury was significant in all biological media. The high-consumption group had much higher mercury levels in blood (9-fold), hair (7-fold), alveolar air (3-fold), and urine (15-fold) than the low-consumption group. The latter finding may be explained by demethylation of methylmercury in the body. The ratio between mercury concentration in blood and hair was 1:270. This implies that the typical blood-hair ratio of 1:250, specified by the World Health Organization (WHO) in 1990, is valid also for exposure to low amounts of methylmercury.     

Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys.

We developed a fusion toxin consisting of the catalytic and translocation domains of diphtheria toxin linked to human granulocyte-macrophage colony-stimulating factor (GM-CSF) (DTGM) for the treatment of patients with acute myeloid leukemia (AML). Our goal in this study was to determine the toxicity and pharmacokinetics of DTGM in cynomolgus monkeys (Macacca fascicularis), which possess cross-reactive GM-CSF receptors. Four groups of young adult monkeys (6 males and 12 females) were treated with five daily bolus iv infusions of 1, 5, 7.5, and 10 microgram/kg DTGM. Monkeys (2 males and 2 females) treated at 1 microgram/kg/day showed no significant side effects. Monkeys (2 males and 2 females) treated at 5 microgram/kg/day showed Grade 1-2 thrombopenia (NCI common toxicity criteria) on day 9. In contrast, monkeys (6 females) treated at 7.5 microgram/kg/day developed Grade 3 neutropenia, Grade 1-2 thrombopenia, Grade 1-3 anemia, and Grade 1-3 hypoalbuminemia. The neutropenia developed by day 4 in the 7.5 microgram/kg/day monkeys and by day 3 or 5 in the 10 microgram/kg/day monkeys and resolved in both groups by day 9, but the thrombopenia, anemia, and hypoalbuminemia persisted until day 16. Monkeys (2 male and 2 female) treated with 10 microgram/kg/day showed Grade 4 neutropenia that resolved by day 8 and Grade 2-3 anemia, hypoalbuminemia, and thrombopenia. Three of the animals developed sepsis. DTGM plasma half-life was 30 min with a peak concentration of 0.1 microgram/mL or 2 nM (1000-fold higher than the IC50 in vitro for AML blasts). Immune responses were minimal in all animals tested at 14 and 28 days with anti-DTGM levels <1 microgram/mL. All four animals at 10 microgram/kg died or were euthanized, and necropsies were performed. Animals necropsied on days 4 and 6 showed marked apoptosis and hypoplasia in the marrow, which was completely resolved for animals necropsied on day 9. No injury to other organs, including kidney, heart, liver, central nervous system, or lung, was seen. The drug was selectively toxic to malignant or differentiated myeloid cells with little toxicity to myeloid progenitors or other organs. Minimal effects in nontarget tissues make DTGM a promising candidate chemotherapeutic agent.     

Multiple aspects of hair analysis for opiates: methodology, clinical and workplace populations, codeine, and poppy seed ingestion

Levels of morphine, 6-monoacetylmorphine (MAM) and codeine in hair in both clinical and workplace subjects are presented. Aggressive wash procedures, consisting of 1 isopropanol wash, three 30-min, and two 1-h buffer washes, followed by digestion, extraction and confirmation of digested samples, resulted in values from the cutoff of 2 ng morphine/10 mg hair to greater than 200 ng/10 mg hair. Both morphine and MAM were present above the cutoff in all hair samples from 69 clinical subjects. Only 39 of the 69 heroin-using subjects had urine tests positive for 6-MAM. In a study of morphine in hair following poppy seed consumption, ten subjects ingested 150 g of poppy seed over 3 weeks. Urine samples were collected on the days of poppy seed ingestion and hair samples were taken in the 5th week of the study. The range among the 10 subjects of the highest urine value for each subject was 2929 to 13,827 ng morphine/mL. Hair morphine levels were 0.05-0.48 ng/10 mg hair (average 0.17 ng/10 mg hair). Hair opiate levels of workplace subjects ranged somewhat lower than those of clinical subjects. While all clinical hair samples contained MAM, many workplace samples did not. From workplace samples, a maximum amount of morphine likely to be present from codeine use was 0-3.7% of the codeine in the hair.     

Developmental and sex differences in cadmium distribution and metallothionein induction and localization

Age- and sex-related differences in hepatic and renal distribution of cadmium (Cd) and the effect of Cd injection (10 mumol/kg) on tissue zinc (Zn), copper (Cu) and metallothionein (MT) levels were investigated in 2- to 84-day old rats. Renal Cd accumulation increased with age of the animal. Sex differences in renal Cd accumulation were noted in young animals where the 2- and 8-day old males had significantly greater concentration than the females. There were no clear effects of Cd on renal Zn. Renal Cu levels, however, were elevated in the adults. The adult females contained about twice as much MT as the adult males. Cd treatment had no effect on renal MT levels of 8- to 84-day old animals but depressed the levels in 2-day old. Age-related increase in hepatic Cd accumulation was also found; the pattern was more clear cut in females than in males. In addition, in the females the hepatic Cd concentration was significantly higher than in the males. Cd-injection significantly increased hepatic Zn and MT concentrations only in weaned animals. While there were no sex differences in MT levels in the young animals, the weaned females had significantly more MT than the corresponding males. Immunohistochemical staining for MT showed positive staining in both cytoplasm and nuclei of the parenchymal cells. The number of MT-positive nuclei was dependent on the relative MT concentration of the liver. In spite of the intense nuclear staining in 2-day old controls and 84-day old Cd-injected rats, less than 1% of the hepatic MT was present in the nuclear fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Uptake of aluminum, cadmium, copper, lead, and zinc by human scalp hair and elution of the adsorbed metals

Uptake of aluminum (Al), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) from aqueous solutions by human scalp hair (water/hair = 100:1) has been studied in the concentration range 0-50 mg/L. Hair metal levels were determined by a wet digestion procedure and atomic absorption spectrometry. Under conditions used, uptake followed a sigmoid concentration-response relationship. The order of binding capacity of hair to the metals was as follows: Al greater than Cd greater than Cu greater than Pb greater than Zn. Using logit transformation 50% saturation was evaluated at the following metal concentrations (hair metal concentration of saturation is given in parenthesis): 0.34 mg/L for Al (0.154 mg/g); 1.82 mg/L for Cd (0.363 mg/g); 2.21 mg/L for Cu (0.651 mg/g); 2.52 mg/L for Pb (0.986 mg/g); 23.84 mg/L for Zn (1.616 mg/g). Percentage elution of trace metals from hair after treatment with metal-enriched solutions by five different procedures ranged from 14.5 to 46.5% for Al, from 11.1 to 28.9% for Zn, from 11.5 to 28.4% for Pb, from 8.9 to 13.6% for Cd, and from 0.1 to 11.8% for Cu. In addition, trace element concentrations were measured in tap water samples and shampoos.     

Concentration and reference interval of trace elements in human hair from students living in Palermo, Sicily (Italy)

Trace element contents in specimens of hair collected from 137 children aged 11-13 years old, living in Palermo (Sicily, Italy) were determined by ICP-MS. This work reports analytical data for the following 19 elements: Al, As, Ba, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, U, V and Zn. The most abundant chemical elements were zinc and copper (Zn > Cu), with concentrations exceeding 10 μg/g (Zn = 189.2 μg/g; Cu = 22.9 μg/g). Other elements with concentrations greater than 1 μg/g were, in order of abundance, Al>Sr>Ba>Pb. The remaining elements were all below 1 μg/g. The average elemental concentrations in hair were statistically compared by Kolmogorov-Smirnov's test taking children's gender into account. Al, Ba, Cr, Li, Rb, Sb, Sr, V and Zn were statistically different according to gender, with significance p < 0.001. This study thus confirms the need for hair analysis to differentiate female data from those of males. IUPAC coverage intervals and coverage uncertainties for trace elements in the analysed hair samples are also reported.     

Renal and hepatic accumulation of cadmium and lead in the expression of CYP4F2 and CYP2E1

The present study examined accumulation of the metal toxins cadmium (Cd) and lead (Pb) in relation to the abundance of cytochrome P450 4F2 (CYP4F2), CYP2E1 and concentrations of zinc and copper in liver and kidney samples using immunoblotting coupled with metal analysis. The post mortem liver and kidney cortex samples were from 23 males and 8 females aged 3-89 years. All were Caucasians who had not been exposed to metals in the workplace. Average kidney cortex Cd load of 17.4 microg/g w.w. was 17 times greater than average liver Cd load (1.1 microg/g w.w.). In contrast, average kidney cortex Pb load of 0.09 microg/g w.w. was two times lower than liver Pb load of 0.19 microg/g w.w. Average Zn and Cu concentrations in the kidney cortex samples were 67% and 33% lower than those in the liver. Liver and kidney Cd loads, but not liver or kidney Pb loads, correlated positively with donors' age. After controlling for liver Cd load, an inverse correlation was seen between Zn and age (partial r=-0.39, P=0.02), suggesting reduction in liver Zn levels in old age. Liver CYP2E1 protein abundance correlated with age-adjusted Cd load (partial r=0.37, P=0.02) whereas kidney CYP4F2 protein abundance showed a positive correlation with age-adjusted Cd loads (partial r=0.40, P=0.02). These findings suggest that Cd may be an inducer of renal CYP4F2 and hepatic CYP2E1 and that increased renal CYP4F2 expression may implicate in Cd-linked renal tubular dysfunction and high blood pressure, involving CYP4F2-dependent arachidonic acid metabolism.     

Toxicokinetics of the mycotoxin ochratoxin A in F 344 rats after oral administration

Ochratoxin A (OTA), a mycotoxin produced by several fungi of Aspergillus and Penicillium species, is a nephrotoxin and a renal carcinogen in rodents. This study was performed to investigate the biotransformation and toxicokinetics of this important food contaminant. Male (n=18) and female (n=18) F344 rats were administered a single dose of OTA (0.5 mg/kg b.w.) in corn oil by gavage. Animals (n=3) were sacrificed 24, 48, 72, 96, 672, and 1,344 hours after OTA administration and concentrations of OTA and OTA-metabolites in urine, feces, blood, liver, and kidney were determined by HPLC with fluorescence detection and/or by LC-MS/MS. Recovery of unchanged OTA in urine amounted to 2.1% of dose in males and 5.2% in females within 96 h. In feces, only 5.5% respectively 1.5% of dose were recovered. The major metabolite detected was OTalpha; low concentrations of OTA-glucosides were also present in urine. The maximal blood levels of OTA were observed between 24 and 48 h after administration and were appromixately 4.6 micromol/l in males and 6.0 micromol/l in females. Elimination of OTA from blood followed first-order kinetics with a half-life of approximately 230 h. In liver of both male and female rats, OTA-concentrations were less than 12 pmol/g tissue, with a maximum at 24 h after administration. In contrast, OTA accumulated in the kidneys, reaching a concentration of 480 pmol/g tissue in males 24 h after OTA-administration. Generally, tissue concentrations in males were higher than in females. OTalpha was not detected in liver and kidney tissue of rats administered OTA, and the OTalpha concentrations in blood were low (10-15 nmol/l). The high concentrations of OTA in kidneys of male rats may, in part, explain the organ- and gender-specific toxicity of OTA.     

Acute and sub-acute inhalation toxicity of germanium metal powder in rats

An acute (4-hr) and a sub-acute (4-wk) inhalation toxicity study of germanium metal powder (purity 99.8%, mean particle size 2.0-2.4 microns) were carried out in young adult Wistar rats. Exposure of five male and five female rats to 3.86 or 5.34 g/m3 for 4 hr resulted in the death of one rat at each exposure level. Four groups of five male and five female rats were exposed to 0, 9.9, 65.1 or 251.4 mg/m3 for 6 hr/day, 5 days/wk for 30 days. Two additional (recovery) groups of five male and five female rats exposed to 0 or 251.4 mg/m3 were kept untreated for 31 days after exposure. At the end of the treatment period, fasting blood glucose was decreased in males exposed to the high concentration. In females of this group, blood creatinine and urea levels, and urine volumes were increased, but urine density was decreased. Increased blood creatinine levels and urine volume and decreased urine density were also observed in females exposed to 65.1 mg/m3. The absolute and relative lung weights were increased in rats in the mid-and high-concentration groups. Histopathological examination revealed: accumulation of particulate material in the lungs of all treated groups, accumulation of alveolar macrophages in the mid- and high-concentration groups, and alveolitis mainly in the high-concentration group. After the 4-wk recovery period, urine volume was increased in males that had been exposed to germanium. In exposed rats of both sexes, lung weights were still increased and histopathological changes were present, but to a lesser extent than at the end of the exposure period. It was concluded that the 4-hr LC50 value of germanium metal powder in rats is greater than 5.34 g/m3. The no-adverse-effect level in the 4-wk study was 9.9 mg/m3 air.     

Influence of long-term exposure to dietary cadmium on growth, maturation and reproduction of goldfish (subspecies: Prussian carp Carassius auratus gibelio B.)

The influence of long-term exposure of goldfish to dietary cadmium (Cd) on its accumulation in tissues, growth, ovarian development, luteinizing hormone (LH) secretion and a response to hormonal stimulation of spawning were evaluated. The study was conducted on four groups of females for the period of 3 years, from the age of 10 weeks to second spawning. Four doses of Cd were applied in the feed: 0 (control group), 0.1, 1 and 10 mg Cd g(-1) of feed (wet weight). The highest dose of Cd (10 mg g(-1)) inhibited growth and caused several behavioural effects. In contrast, lower dose of Cd (1 mg g(-1)) stimulated fish growth. The doses of Cd from 0.1 to 1 mg Cd g(-1) did not influence ovarian development. The gonado-somatic index (GSI) and histological analysis of ovaries showed no differences in ovarian development between the control group and the groups receiving these doses of Cd. However, in the group receiving the highest Cd dose, GSI decreased. This was associated with persistent, long-lasting elevation of plasma LH levels. Ovulation did not occur in this group. Injections of salmon GnRH-analogue (sGnRHa) alone or with domperidone (a dopamine receptor antagonist) in sexually mature fish caused an increase of LH levels in all groups, although in the group fed with the highest Cd dose the effect was weaker than in the other groups. After the first spawning season, a negative effect of lower Cd doses (0.1 and 1mg Cd g(-1)) on ovarian recrudescence (rebuilding of ovaries) and on the response to the consecutive hormonal stimulation of spawning was observed (lower number of ovulating females). There was a significantly higher content of Cd in the livers of fish than in their muscles. The results of hormonal stimulation of spawning and histological analysis of ovaries suggest that in goldfish cadmium acts mainly at the level of ovary rather than on the pituitary gland. We suppose that in the natural environment cadmium present in the feed can play an important role in the accumulation of this element in fish tissues and can influence vital physiological processes.     

Estrogen-dependent differences in the acetylation of sulfadimidine in the rat

The influence of sex hormones on the acetylation of sulfadimidine was investigated in male and female rats, both intact and castrated. Sulfadimidine was administered intravenously in the dose of 40 mg/kg body weight, and unchanged and acetylated sulfadimidine (Ac-S) were then determined in urine and blood. It was found that the percentage of Ac-S was significantly higher in the urine of females than males. The concentration of sulfadimidine in blood was also higher in females than in males. While estrogenization raised the percentage of Ac-S in the urine of males and the concentration of unchanged sulfadimidine in blood, treatment with an androgen had no significant effect in females. The long-lasting stimulatory influence of estrogen in males and a normal percentage of Ac-S in gonadectomized females suggest an indirect action of estrogen. Possible mechanisms are discussed.     

Carcinogenic effects of antimony trioxide and antimony ore concentrate in rats

This study was initiated because of a suspected increase in incidence of lung cancer in antimony smelter workers in England. Three groups of 8-mo-old Wistar-derived rats (90 males and 90 females per group) were exposed by inhalation to either Sb2O3 [time-weighted average (TWA) 45 mg/m3], Sb ore concentrate (TWA 36 + 40 mg/m3), or filtered air (controls) for 7 h/d, 5 d/wk, for up to 52 wk and sacrificed 20 wk after terminating exposures. Serial sacrifices (5 rats/sex/group) were performed at 6, 9, and 12 mo. Autopsies and histopathological examinations were performed on all animals. The dusts and animal tissues were analyzed for Sb, arsenic, and other inorganic elements by atomic absorption and proton-induced X-ray emission methods. The most significant findings were the presence of lung neoplasms in 27% of females exposed to Sb2O3 and 25% of females exposed to Sb ore concentrate (p less than 0.01). None of the male rats in any group or the female controls developed lung neoplasms. There were no significant differences in incidences of cancer of other organs between exposed and control rats. These results were compared with other published results, including an animal inhalation study with Sb2O3 in which lung tumors were also induced. Higher concentrations of arsenic were found in tissues from female rats than from male rats. For example, arsenic levels in blood of control males, control females, Sb2O3 males, Sb2O3 females, Sb ore males, and Sb ore females were 60, 123, 115, 230, 71, and 165 micrograms arsenic/g dry blood, respectively, 9 mo after initiating exposures.     

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.