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The objective of this study was to estimate the relationships between cadmium (Cd) levels in the small intestine and other organs (kidney, liver, lungs) and factors influencing the intestinal Cd levels in humans, as based on autopsy analysis of subjects not exposed to Cd occupationally. The study also involved estimating the levels of zinc (Zn) in these organs, as it is known that this element exerts interactions with Cd at the level of absorption and tissue binding. The levels of Cd and Zn were determined in the renal cortex, liver, lungs and three fragments of the small intestine (duodenum, jejunum, ileum) of 29 subjects deceased at the age 42 +/- 13 years. Flame atomic absorption spectrometry (AAS; kidneys, liver) and flameless AAS (lungs, intestine) were used. The level of Cd in the lungs was used as a marker of smoking habit. The determined levels (mean +/- SD) were: 0.28 +/- 0.16 microg Cd/g and 15.2 +/- 3.4 microg Zn/g in the duodenum; 0.26 +/- 0.15 microg Cd/g and 16.9 +/- 3.7 microg Zn/g in the jejunum; 0.13 +/- 0.07 microg Cd/g and 14.6 +/- 5.4 microg Zn/g in the ileum. Intestinal Cd levels are correlated with organ and total body Cd, and this was best expressed for Cd in ileum (r=0.67 with renal, r=0.71 with hepatic and r=0.68 with total Cd). In conclusions, the levels of Cd in the small intestine of humans are relatively low and reflect predominantly the whole body retention of this element. Somewhat higher levels of Cd are contained in the initial parts of the small intestines. In all fragments of small intestines the levels of Cd are higher in smokers. Also, the levels of Zn were relatively low and did not correlate with the levels of Cd.

The present report aims at providing broader information on the acute nephrotoxicity of 2-bromophenol (2-BP) (a bromobenzene (BB) metabolite), due to its action on the kidneys, after repeated administration. Investigations were performed on female rats. Following a single dose, the most pronounced changes involved: concentrations and rates of excretion of proteins in urine, the number of epithelial cells excreted in urine, creatinine and urea clearance and reduced glutathione in renal tissue. Immediate effects could be ascribed to both renal tubules and glomeruli, mirrored in the level of urinary proteins and intensified excretion of renal epithelial cells. Less pronounced changes of the indicator values were noted under repeated dosing of 2-BP. The results obtained in a single exposure study confirm earlier reports on the mild nephrotoxicity of 2-BP following exposure to high doses. However, the transition from single to repeated exposure does not result in enhanced nephrotoxicity.

The distribution, excretion and metabolism of 1,4-dibromobenzene (1,4-DBB) and 1,2-dibromobenzene (1,2-DBB), following a single intraperitoneal administration to female Wistar rats, were investigated using radiotracer 3H and GC-MS technique. The maximum level of 3H after 1,4-DBB administration was detected in all examined rat tissues between 4 and 24 h foltowing the injection. The highest concentrations of 3H were found in fat tissue, muscles, adrenal glands and sciatic nerve. About 50% of administered dose was still retained in the rat 72 h after injection. For 1,2-DBB, the highest level of 3H was in the liver, kidneys and fat tissue 4 and 8 h after administration. Three days after injection, less than 2% of the given dose was retained in the rat body. Urine turned out to be the main route of 3H excretion following the injection of both compounds (30% and 82%, after 1,4-DBB and 1,2-DBB, respectively), and about 4% of the given dose was excreted in feces. In urine of rats the following substances were identified (in sequence 1,4-dBB and 1,2-dBB): (1) unchanged parent compounds (5 and 11%); (2) dibromophenols (84 and 73%); (3) dibromothiophenols (5 and 10%) and (4) monobromophenols (1.9 and 0.7%). This study suggests that 1,2-DBB is characterized by a relatively high turnover rate, whereas 1,4-DBB shows a tendency for long-term retention in the body.

The aim of the study was to determine whether monobromobenzene (BB) and hexabromobenzene (HBB) administered repeatedly (for 28 days) to female rats resulted in disturbances of heme synthesis. 5-Aminolevulinate dehydratase (ALA-D) and 5-aminolevulinate synthase (ALA-S) activities were slightly changed and the concentration of glutathione increased. The excretion of 5-aminolevulinic acid (ALA-U) in urine after all doses of BB and HBB increased already in the first week. After BB administration, increased excretion of coproporphyrins was detected only at the highest dose. The increased excretion of coproporphyrins following the administration of HBB could be observed already at the lowest dose (15 mg/kg). The excretion of uroporphyrins increased after two higher doses (75 and 375 mg/kg) in the fourth week of exposure. HBB also caused elevation of microsomal P450 level. The data suggest porphyrogenic activity of HBB; whereas in the case of BB we cannot exclude that elevated excretion of ALA-U resulted from kidney impairment.

Tetrabromobisphenol-A (TBBP-A) is used as a reactive flame retardant and as an intermediate in the production of other flame-retardants. In our study, TBBP-A was administered intragastrically, daily for 7 or 7-28 days at three dose levels. Significant changes of biochemical indicators were noted with regard to glutathione (GSH), malondialdehyde (MDA) and 5-aminolevulinate dehydratase (ALA-D). The level of GSH was lowered by the two higher doses (female rats only) and MDA was elevated by the highest dose (male rats only). The ALA-D activity reacted in opposite directions for both sexes. Other indicators did not yield any conclusive results. The 28-day study was performed on female rats. For GSH and MDA the medium dose resulted in a systematic increase. Insignificant changes in ALA-D activity in the liver were observed throughout the experiment. The activity of 5-aminolevulinate synthase had a decreasing tendency at 250 mg/kg of TBBP-A during the whole time of observation. Other general indices such as the activity of gamma-glutamyltransferase, concentration of microsomal proteins and the level of cytochrome P-450 did not show any significant changes. The most pronounced changes were noted with regard to indicators of porphyrogenic action. The results suggest that TBBP-A is capable of disturbing the heme metabolism in rats.

Male mice of Balb/C strain were administered i.p. carbon tetrachloride, in single doses of 35 and 145 mg/kg, given at variable time of the day. The activity of alanine aminotransferase (ALAT) in serum, and the hepatic level of malondialdehyde (MDA) as well as reduced glutathione (GSH) were adopted as indicators of toxicity. In selected groups, liver histopathology was carried out. The experiment was performed in two series differing in the dynamics of observations. A differentiation of the intensity of toxic effects was found dependent on the time of the day at which animals were administered the xenobiotic. This was especially evident for a lower dose: given in the morning it produced no effects, whereas given in the evening it resulted in distinct elevation of toxicity indicators. Additionally, the correlation was checked between the histopathological evaluation (semiquantitative expression) and serum ALAT activity. A high correlation (r = 0.98) allows for basing the evaluation of liver necrosis on the ALAT activity alone.

The distribution, excretion and metabolism of 1,3-dibromobenzene following a single i.p. administration to rats 100 or 300 mg/kg was investigated using radiotracer [3H] and GC-MS technique. After 72 hours about 74 to 90% were excreted in urine. The highest radioactivity was observed in the liver, kidneys and fat tissue. Later on a steady decline of radioactivity was apparent in all investigated tissues except for blood cells and the sciatic nerve, where constant levels were noted. In urine the following substances were identified and quantified by GC peak areas: unchanged 1,3-DBB (18%), dibromophenols (34%), dibromothiophenols (28%), dibromothioanisole (1.8%), bromophenol (5.5%), bromohydroxythiophenols (5%), and bromohydroxythioanisole (7.5%).

This article is based on data on the levels of metals (Cd, Zn, Cu) and metallothionein (MT) determined radiochemically with 203Hg in renal cortex and liver of 137 autopsy cases. From this number, for 23 cases, the gel filtration of the cytoplasmic fraction of the organs was performed. The molar content of metals in the MT fraction (Sephadex G-50) amounted to 46.9, 50.2, and 2.0% for Cd, Zn, and Cu in renal cortex, respectively, and to 8.3, 83.6, and 9.1% for Cd, Zn, and Cu in the liver, respectively. In parallel with the increase of Cd and MT in renal cortex, increasing saturation was found of the MT fraction by Cd, occurring at the expense of Zn and Cu. Equimolar amounts of Cd and Zn in the MT fraction are found at Cd level of 0.5 micromol Cd/g wet wt of renal cortex. In the liver, analogous dependency (elevation of %Zn, depression of %Cd and %Cu) were observed in relation to Zn and MT levels in this organ. The basic level of Zn (not bound with MT) was estimated at 0.5 micromol/g for both renal cortex and liver. A deficit of non-MT Zn in kidneys is proposed as an alternative mechanism of toxic Cd action.

Objective: To estimate the equivalent cadmium levels in renal cortex and in urine, as based on autopsy analysis of subjects not exposed to cadmium occupationally., Methods: The levels of Cd were determined in renal cortex, liver, urine and urinary bladder of 39 subjects deceased at the age 42 +/- 14 years. Flame atomic absorption spectrometry (kidneys, liver) and flameless AAS (urine, bladder) were used., Results: The urinary cadmium level determined post mortem is strongly correlated with the renal Cd levels. Eliminating cases with high urinary proteins and extrapolating from sets of data with elevated urinary protein concentration to its normal range yielded a value of 1.7 microg/g creatinine as equivalent to the renal level of 50 microg/g w.w., Conclusions: It seems possible to use monitoring data for cadmium in urine and in renal cortex in a coherent way.

Cadmium, zinc and copper levels were determined in the renal cortex and liver of 60 inhabitants of Cracow, Poland. Cadmium levels in the renal cortex were contained in broad limits of 5-176 μg/g, mean 50.6 μg/g (wet weight). Maximum levels were found in the age group of about 50-60 years. The levels were slightly higher in men (53 μg/g) than in women (45 μg/g), with no effect of location within the region. The levels in smokers (62 μg/g) were much higher than in non-smokers (32 μg/g). The above relations were less pronounced for cadmium levels in the liver. Whole body retention of cadmium followed the pattern of cadmium in renal cortex. The level of zinc in renal cortex reflected those of cadmium. A significant proportion of the population (54% in smokers, 9% in non-smokers) showed cadmium levels in renal cortex exceeding the reference level of 50 μg/g recently accepted for general population. In the view of the authors the exposure to cadmium of the population of Cracow is excessive and calls for attention.

Tissues were analysed from 60 subjects deceased at the age of 18-82 (mean 49 years), inhabitants of the southwestern region of Poland (Legnica Copper Basin). Mean cadmium, zinc and copper concentrations determined by flame AAS were for renal cortex 41.8; 47.8 and 2.3 micrograms Me/g tissue, respectively. The respective levels in the liver were 2.3; 51.6 and 4.6 micrograms Me/g tissue (w.w.). A broad range of cadmium levels was found in renal cortex (4.2-129.3.micrograms/g), with the highest values in the 40-60 age group. The effect of tobacco smoking is more evident than in other countries: 26.3 micrograms/g in non-smokers vs. 54.6 micrograms/g in smokers. Similar proportions were found by computing the whole body burden of cadmium. Compared with other regions of Poland the environmental exposure of humans to cadmium is moderate, however, it is higher than in other European countries.

Pentabromophenol (PBP) was administered in a single or repeated doses to mice or in a single dose to rats. Slight changes were noted in the level of SGPT in mice serum and GSH in the liver, with a more pronounced increase of MDA after a single dose. Following repeated administration, gamma-GT and MDA were elevated. The nephrotoxic action of PBP in rats was manifested by the decreased of renal GSH levels, as well as by an increase in protein contents and the number of renal epithelial cells in urine. As a result, limited hepatotoxicity was found only in mice. The nephrotoxicity in rats was comparable with that for 2-bromophenol described earlier.

Mice were administered with chloroform at 10 a.m., 2 p.m. and 6 p.m. and the signs of hepatotoxicity were measured 18 or 24 hrs later. The levels of alanine aminotransferase (ALT) in serum, and malondialdehyde (MDA) in the liver were higher after the evening administration compared to the morning one. The decrements of reduced glutathione (GSH) levels in the liver followed a similar pattern. It is concluded that the susceptibility of mice to the toxic effect of chloroform follows a circadian rhythm.

Cd, Zn, Cu, and metallothionein (MT) levels have been determined in the renal cortex and liver of 70 persons who died in Lodz and its surroundings in the years 1985-1989. The mean concentrations were: 44.9±28.6 µg Cd/g, 52.0±16.7 µg Zn/g, 2.4±1.0 µg Cu/g, 0.79±0.40 µmol Hg/g, and 3.5±1.8 µg Cd/g, 66.7±30.5 µg Zn/g, 4.9±2.1 µg Cu/g, 0.50±0.38 µmol Hg/g wet tissue in renal cortex and liver, respectively, with mean age 54.0±13.8. Smokers showed 2.4 times higher levels of Cd in the renal cortex than non-smokers. The mean body burden of Cd was 33.4±17.3 mg. Smoking increases it twofold from 22.0 mg in non-smokers to 41.8 mg in smokers.

The levels of Cd, Zn, Cu and metallothionein (MT) were determined in renal cortex and liver of 75 subjects decreased in the period 1986-1989 in the area of Upper Silesia (Katowice). The mean age of the population studied was 53.6 +/- 14.6 years. The determined levels (mean +/- SD) were: 43.1 +/- 23.5 micrograms Cd/g; 52.5 +/- 17.4 micrograms Zn/g; 2.2 +/- 0.7 microgram Cu/g; 0.80 +/- 0.36 mumol Hg/g in renal cortex and 3.5 +/- 2.5 micrograms Cd/g; 82.8 +/- 34.3 micrograms Zn/g; 4.5 +/- 2.6 micrograms Cu/g; 0.69 +/- 0.44 mumol Hg/g in the liver. The level of Cd in renal cortex was 40% higher in smokers compared to nonsmokers and was independent of the gender. Whole-body retention of Cd was 34.1 +/- 18.5 mg; smoking elevated the value from 27.1 to 38.2 mg. Compared with a similar study made in central Poland (Lódź), a significant difference was found only regarding the level of Zn and MT in the liver, pointing to the possibility that exposure to this element in the region of Upper Silesia may be higher.

Concentrations of Cd, Zn, and Cu were determined in the renal cortex and the liver of 79 persons who died in 1991 in Białystok and its vicinity. The mean concentrations were: 30.5 +/- 27.7 micrograms Cd/g, 37.6 +/- 18.5 micrograms Zn/g, 2.6 +/- 2.5 micrograms Cu/g, and 2.1 +/- 2.2 micrograms Cd/g, 52.4 +/- 20.5 micrograms Zn/g, 4.0 +/- 2.1 micrograms Cu/g, respectively, in the renal cortex and the liver, at the mean age of 51.1 +/- 19.1 years. Smokers showed almost twice higher Cd levels in the cortex than non-smokers. The mean whole body retention calculated for cadmium was 18.9 +/- 15.9 mg. Smoking increases it by about 60%--from 13.7 mg in non-smokers to 22.8 mg in smokers. In the inhabitants of the investigated region cadmium levels (kidney, liver, whole body retention) were lower than in persons from Lodz and Katowice regions.

This report presents a set of investigations on the hepatotoxic action of acetaminophen (AA). Male mice of Balb C strain were given [3H]acetaminophen in doses of 100, 300 and 600 mg kg-1 with or without pretreatment with 3-methylcholanthrene (3MCh) or diethyl maleate (DEM). The results of this study show that AA administered in moderate doses brings about necrotic changes due to adduct formation with macromolecules. Adduct formation was inversely correlated with the level of glutathione. Both modifiers enhanced hepatic necrosis and lethality. Diethyl maleate exerted these effects without enhancing covalent binding to macromolecules, while 3MCh increased both adduct formation and lipid peroxidation.

203Hg-Mercuric chloride was administered intragastrically to female rats. The absorption rate evaluated for a broad range of doses was found constant for low and medium range, and higher for high doses. Mercury was determined in internal organs and intestines. The time-course of intestinal mercury indicated that a deposit formed initially in the mucosa was further absorbed into the circulation. No indication was found of a protection mechanism based on exfoliation of the mucosal deposits of metal.

Mice of the Balb'c strain were administered bromobenzene (BB) or acetaminophen (AA) i.p., in single doses of 400 and 300 mg/kg, respectively. In the blood activity of SGOT and SGPT as well as SDH was determined. In the liver the level of metallothionein (MT), malondialdehyde (MDA) and glutathione (GSH) was measured. The level of MT as well as GSH (determined as non-protein SH groups) showed a significant increase following administration of zinc alone. Joint action of zinc and either BB or AA resulted in a decrease of GSH which was less pronounced than expected for each of the xenobiotics alone. The protective effect of zinc reflected in the reduction of the increase of SGPT and SGOT activity was apparent shortly (4 h) after administration of AA. A day after injection of AA alone the activity of enzymes was lower and the rate of decline followed the sequence SGPT greater than SGOT greater than SDH. For BB, both the toxic effect and the protective influence of zinc were apparent 24 h following administration. At 4 h in a group receiving BB alone no changes of the indicatory enzymes in blood were noted.

The possibility of evaluating occupational exposure to toluene at low levels (50-150 mg/m3), based on the determination of unchanged substances in capillary blood, was investigated. The volunteers were exposed in a toxicological chamber; during and after exposure venous and capillary blood samples were analysed by gas chromatography using the headspace technique. Toxicokinetic data point out that determination of toluene should be performed in blood samples collected 15-20 min after termination of exposure. The toluene concentration in capillary blood may reflect the toluene dose absorbed during the workshift only in the case of constant exposure. Otherwise, this measurement refers to the rate of toluene absorption, mainly in the last 2 hours of daily exposure.

Chloroform was administered ip to Balb/c mice as a single dose ranging from 1/8 to 1 of the approximate lethal dose. At different time periods after administration, mice were sacrificed. Serum glutamate-pyruvate transaminase (SGPT) and sorbitol dehydrogenase (SDH) as well as glutathione (GSH) and malondialdehyde (MDA) levels in the liver were determined. Increased SGPT and SDH levels were found for all doses exceeding 1/8 of the approximate lethal dose. The depletion of GSH level was kept within 40% for all doses. A 2-4 fold increase of hepatic MDA level was found. The depletion of hepatic GSH and, to some extent the increase of serum SGPT and SDH, occurred in biphasic fashion. Dose-effect functions for these biochemical alterations could only be constructed for the second, delayed phase of action. It is postulated that the hepatotoxicity of chloroform is mainly dependent on radical formation in the course of biotransformation.

Inorganic mercury, administered to rats in a single dose of 0.5 mg Hg/kg is accumulated in the kidneys mainly in the soluble (54%) and nuclear (30%) fractions, showing decreasing tendency with time. Mitochondrial and microsomal fractions, initially accumulating approx. 11 and 6% of total Hg, show a tendency to increase the absolute level of Hg for the first week after administration. In the soluble fraction low-molecular weight, metallothioneinlike proteins are mainly responsible for the accumulation of mercury, in other fractions proteins of higher molecular weight prevail.

Volunteers (six men and one woman) were exposed by inhalation to styrene within the concentration range of 20 to 200 mg/m3. The average retention of styrene vapours in the respiratory tract was 71%. The yield of styrene metabolism measured within 24 h was 39 and 17% for mandelic acid and phenylglyoxylic acid, respectively. The determination of mandelic acid in urine collected immediately after the exposure was applied as exposure test. The excretion rate of this metabolite assured the best correlation with the absorbed dose. The relative standard deviations of the test related to actual dose level vary, depending on the analysed concentration range, from 0.21 to 0.33. Quantitative interpretation of the test is possible for styrene concentrations in the air exceeding 20 mg/m3. The concentration amounting to 100 mg/m3 (TLV) corresponds with the mandelic acid excretion rate of 15 mg per hour.

The level of metallothionein-like proteins was determined in different tissues of 6 animal species. The highest concentrations were found in pig and rat tissues. The organs richest in metallothionein-like proteins included: kidneys (101-305 microgram/g), intestine (127-257 microgram/g) and liver (54-496 microgram/g).

The intestinal absorption of cadmium and inorganic mercury was studied in adult rats, administered the metal salts intragastrically or parenterally in repeated or single doses. The intestines contained only small proportion of the body burden; no major change was found in the intestinal level of metallothionein, copper and zinc. Therefore, no major role can be ascribed to intestinal metallothionein in limiting absorption of high oral doses of cadmium and mercury.

Absorption of ethylbenzene and excretion of mandelic acid were investigated under controlled conditions in six volunteers, exposed at concentrations of 18, 34, 80, and 200 mg/m3. Retention of ethylbenzene vapours in the lungs was 49 +/- 5%. Elimination of mandelic acid was found to be biphasic, with biological half-life values of 3.1 and 24.5 h. Total excreted mandelic acid accounts for 55 +/- 2% of retained ethylbenzene. The results obtained were applied to devise an exposure test for ethylbenzene, which would enable the precise evaluation of exposure at low ethylbenzene, vapour concentrations (+/- 13%). Exposures, carried out dermally, gave a rationale for the exclusion of the skin as a route of entry of ethylbenzene vapours into the body.

Acetaminophen (AA) was administered i.p. to Swiss mice as a single dose 100, 200, 300, 400 and 600 mg/kg. At different time periods after administration, the mice were sacrificed. Serum glutamate-pyruvate transaminase (SGPT) and sorbitol dehydrogenase (SDH) as well as glutathione (GSH) levels in the liver were determined. It was found that the effective dose ranged within 200-600 mg/kg. Changes in GSH level occurred shortly after acetaminophen administration, whereas changes in the activity of indicatory enzymes were slightly delayed compared to this process. Conditions allowing for parallel observations of all three indices under investigation occurred 4 hrs after acetaminophen administration. With regard to glutathione, directly measured decrease, as compared to control levels, may be used as the yardstick of the changes. Changes in the activity of indicatory enzymes may be better expressed in the dose-response arrangement. For all the indices determined 4 hrs after acetaminophen administration, ED50 is in the range 200-300 mg/kg.

Subcutaneous administration of bismuth, both single and multiple, resulted in deposition of this metal mainly in the kidneys which contained over 50% of the 'accessible pool' of bismuth. In the kidneys bismuth was bound mainly by the soluble fraction in which it was complexed with a protein of molecular weight of about 7000. Multiple administration of bismuth increased the level of this protein. Selenite administration brought about an increase in the 'accessible pool' of bismuth, probably due to a drop in excretion, and also changes in the organ distribution of this metal. The retention in the kidneys was diminished while those in the liver and in other tissues were augmented. These changes were accompanied by a change in the chemical form of bismuth present in the kidneys manifested by the total disappearance of the protein complex of molecular weight of 7000. The increased synthesis of this protein due to bismuth administration was not abolished completely.

1. The effect of low-molecular-weight substances interfering with determination of metallothionein is eliminated by precipitation of 203Hg-thionein by tannic acid. 2. In animals not exposed to metals, the mean values for metallothionein content in liver and kidney are, respectively, 0.10 and 0.18 mg/g in rats, 0.06 and 0.07 in mice and 0.12 and 0.29 in guinea-pigs, i.e. are 2-3 times lower as compared with the values obtained by the procedure not involving treatment with tannic acid.

Three isoforms of mercury-binding, copper-zinc protein were isolated from kidney of rats exposed to mercuric chloride. They contained 56-67 micrograms Hg/mg protein, 23.7-43.9 micrograms Cu/mg and 1.8-5.4 micrograms Zn/mg protein. Amino acid composition of isoforms 1, 2 and 3 was very similar, and also close to that of hepatic [Hg,Zn]- and [Cd,Zn]-metallothionein. Isoforms 1, 2 and 3 contained 29.7, 27.2 and 29.3 mol% cysteine, respectively. The molecular weight of isoforms 1, 2 and 3 was 6580, 6880 and 7000, respectively.

The concentrations of cadmium, zinc, copper and metallothionein in the autopsy samples of liver among the inhabitants of Lódź (Poland) were determined. The cadmium levels were low in the range of 1.5 to 5.8 micrograms/g. The concentration of metallothionein determined by the Hg-method was high (0.160-1.665 mumol Hg/g); it was mainly a Zn-thionein. The percentage of hepatic zinc bound in the MT-fraction increased with the overall content of zinc in the liver. The elevation of zinc in the liver occurs in the proportion required for the saturation of metal-binding ligands of metallothionein. The role of cadmium remains less clear. Our results suggest that the metallothionein level in the liver increase significantly in response to elevated cadmium concentrations. This response, however, is in high excess to the demand which is justified stoichiometrically.

In many situations, the effect of a toxic chemical on a biological system depends on both the intensity and the duration of exposure. The dependence on the time dimension can be the expression of a range of processes including the physical accumulation of toxic chemicals or their metabolites and the functional accumulation of damage. Measures and functions that have been used to describe this dependence are reviewed.Some of these functions are compared through a case study of the neurotoxicity of methylmercury. Use is made of data that indicates a dependency between the blood concentration at which monkeys were exposed and the length of time before damage was detected. Several exposure functions are fitted to these data and their appropriateness is compared. Using the most appropriate function, an exposure-response relationship is developed using probit analysis. An alternative data analysis procedure is also investigated. The apparent threshold after a 100 day exposure is estimated to be greater by a factor of 3-5 compared to the threshold for chronic exposure. Applying this factor to man, the blood concentration threshold for chronic exposure is estimated to be 40-170 ppb, a finding consistent with recent reports of neurological damage in humans exposed below the generally accepted threshold.

Rats were given certain metal salts once every other day for six to eight doses and therafter the levels of metallothionein-like proteins (MTP) were determined in their liver and kidneys. The normal level of those proteins ranged from 0.1 to 0.4 mg/g in the liver and 0.2 and 0.6 mg/g in the kidney. Beryllium, magnesium, barium, strontium, tin, arsenic, selenium, chromium, and nickel administration did not influence the tissue levels of MTP. There was a tendency toward increased MTP levels in the liver after the application of high doses of iron. A significant increase in MTP levels in the liver resulted from cobalt administration and in the kidneys of bismuth-treated rats. Applying molecular filtration it was shown that both metals were partially bound in vivo to protein fractions, the molecular weights of which are close to that of metallothionein.

Renal binding of cadmium was compared in groups of rats administered cadmium intragastrically or subcutaneously in doses resulting in similar renal cadmium concentrations. In rats administered cadmium intragastrically the renal concentrations of copper and metallothionein were lower, suggesting disturbance in copper metabolism. These changes were alleviated gradually in the post-exposure period. In experiments with 64Cu it has been shown that intragastric exposure to cadmium reduced copper absorption to about 21% of that in the control rats, thus explaining the poor copper availability for renal binding of cadmium in the form of Cd,Cu-metallothionein. Changes in zinc uptake were less strongly marked and were limited to slight decrease of zinc content in the kidneys.

Exposure of rats to aniline at daily doses of 50 mg/kg of body weight over a month stimulated the microsomal metabolism as manifested by (1) acceleration of p-hydroxylation of anilin and N-demethylation of aminopyrine in 9-000 times g postmitochondrial supernatant of the liver, (2) shortening the sleeping time after hexobarbital, and (3) reduction of the antipyretic effect of phenacetin. In the rats exposed to nitrobenzene in a similar manner to aniline, nitroreduction of nitrobenzene and p-hydroxylation of aniline remained unaffected; the antipyretic effect of phenacetin was decreased, whereas hexobarbital sleeping time remained unchanged. Exposure of rats to benzene (50 mg/kg of body weight daily for a month) had no effect on the rate of hydroxylation of benzene and N-demethylation of aminopyrine. In benzene-exposed rats hexobarbital sleeping time was prolonged whereas the antipyretic effect of phenacetin was unaffected. Microsomal metabolism of aniline, nitrobenzene, and benzene was stimulated and inhibited when the rats were pretreated with phenobarbital and SKF 525-A, respectively.

The area of Upper Silesia is the most industrialized region in Poland. The concentrations of cadmium (Cd), zinc (Zn), copper (Cu) and metallothionein (MT) in autopsy samples (n = 29) of liver from the inhabitants of that area were determined. The metal levels varied in the ranges of 0.5-11.9 micrograms Cd/g, 45.3-221.6 micrograms Zn/g, 1.4-10.3 micrograms Cu/g. The concentration of MT determined by the Hg-method was high: 0.38-2.86 mumol Hg/g. A positive linear relationship was observed between Zn and MT levels.

The study critically reviews recent data relating to the health effects of methylmercury in man and the attendant dose-response relationships. New data obtained from animal studies, including pre-and postnatal exposure, are also examined. The consumption of fish and fish produce represents the major source of methylmercury exposure in the general population. Reported mercury concentrations in fish throughout the world are examined, particularly in the Mediterranean Sea. Here there is limited knowledge of methylmercury intake in critically exposed populations such as fishermen, employees of the fish industries and their families. The measurement of mercury in hair is now regarded as the most useful indicator of exposure but more experimental data are still required to increase the value of this index. The threshold levels of methylmercury in blood, hair and for dietary intake, as estimated by the World Health Organization, have been largely endorsed. However, new information from Japan and Canada suggests the existence of a latency period for some effects, so that the frequency or probability of their occurrence is inversely related to the duration of exposure. Incorporation of such findings would therefore lead to the designation of lower threshold values than are presently recognized. Pregnant women and the fetus have been identified as groups that are at special risk. The fetal blood mercury level is up to twice that of the mother and the sensitivity of both mother and fetus may be higher than in non-pregnant adults. This should be taken into account when assigning protective threshold concentrations.