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The dose-effect relationship between cadmium exposure and blood pressure was reviewed citing 67 references. Results indicated that prolonged administration of a low cadmium dose may elevate blood pressure slightly, whereas a higher dose may depress blood pressure, but only in hypertensive humans and animals. Cadmium tends not to change the blood pressure of normotensive humans or animals. These conclusions suggest that cadmium affects only hypertensive cadmium workers. The general public exposed to cadmium at lower dose levels should be advised to restrict cholesterol intake to avoid the risk of hypertension through cadmium-accelerated atherosclerosis. J. Trace Elem. Exp. Med. 13:155–163, 2000. © 2000 Wiley-Liss, Inc.

Thirteen rabbits were given subcutaneous cadmium (0.3 mg Cd/kg) daily. The plasma cadmium–metallothionein (CdMT) and the Cd-induced hepatic and renal functions were determined at 0, 5, 8, 11, 12, 13 and 14 weeks. Hepatic dysfunction, an elevated plasma CdMT and renal dysfunction were detected mostly between 12 and 14 weeks. The hepatic dysfunction parameters were closely related with the plasma CdMT, which was then found to correlate with the renal dysfunction parameters. All the above findings suggest the following mechanism for the Cd-induced renal dysfunction: hepatic CdMT is released into the plasma upon the Cd-induced hepatic dysfunction, and then excess plasma CdMT, whose concentration is proportional to the CdMT in the renal proximal tubular lumen, induces renal dysfunction. The critical concentration of plasma CdMT to induce renal dysfunction was estimated as 80 μg Cd/l. The plasma CdMT is proposed therefore as a biological exposure index for the Cd-induced renal dysfunction, based on the mechanism of its action.

Cadmium-induced renal dysfunction has hitherto been regarded as noncurative, with the renal dysfunction occurring when the cadmium concentration in the renal cortex exceeded a critical concentration for the renal cortex, 200 μg/g wet weight. However, we have identified a mechanism that is quite different from the above working hypothesis: cadmium induces hepatic dysfunction through cadmium-induced free radicals in the liver. Hepatic cadmium-thionein is released into the bloodstream upon hepatic dysfunction and enters the renal tubular lumen by freely passing through the renal glomeruli to result in injury to the brush border membrane of the proximal convoluted tubules. The critical concentration of plasma cadmium, an alternative biomarker for cadmium-thionein in the renal proximal tubules, for inducing renal dysfunction was found to be 100 &mu Cd/L and was quite independent of the cadmium level in the renal cortex. Cadmium-induced renal dysfunction was therefore considered reversible following cessation of cadmium exposure, when the renal dysfunction was not so serious, probably as a result of decreased levels of plasma cadmium-thionein. We also succeeded in improving cadmium-induced renal dysfunction through subcutaneous glycyrrhizin administrations, by lowering the plasma cadmium-thionein due to alleviation of the destruction of hepatic cells. We further succeeded in ameliorating cadmium-induced renal dysfunction through administration of acetazolamide, a carbonic anhydrase blocker, due to the depressed plasma cadmium-thionein associated with improvement of the hepatic dysfunction. J. Trace Elem. Exp. Med. 11:275–288, 1998. © 1998 Wiley-Liss, Inc.

To elucidate the sex difference in porphyrin metabolic disorders induced by lead exposure, we determined plasma delta-aminolevulinic acid (ALA), urinary ALA, and urinary coproporphyrin (CP) in 298 lead-exposed workers (160 males and 138 females), and compared the data thus obtained. The use of fluorometric high-performance liquid chromatography (HPLC) method which is highly sensitive and specific made possible the measurement of ALA in a small volume (50 microliters) of plasma. The concentrations (mean +/- SD) of lead in blood (males: 55.1 +/- 12.9 micrograms/dl; females: 54.7 +/- 13.5 micrograms/dl) indicated that the intensity of occupational exposure to lead was almost equal in the two groups. However, the elevation of plasma ALA concentration and the increased urine ALA and CP excretion among these lead workers were much higher in females than in males, confirming the finding of a sex difference in the biological effect of human exposure. The difference in urine CP excretion was especially pronounced, the mean concentration of urinary CP in the female workers being 3.5-5 times higher than that in the male workers.

1) ZINC: In 1963, Prasad found that dwarfism in Egypt was caused by zinc deficiency. Since then, many clinical pictures involving zinc deficiency have been reported on, such as alopecia (baldness), intestinal acrodermatitis (dermatitis of the extremities), alcohol-induced anencephalic children, and depressed immune response. 2) COPPER: Wilson’s disease is characterized by hepato-cerebral degeneration, which is caused by the deposition of copper in the liver and the cerebrum. Chelete therapy has been applied to remove the copper from the organs in order to treat Wilson’s disease. However, during the last several years zinc or manganese has also been applied to remove copper. The therapy mechanism is based on the interaction of copper to zinc and manganese. Zinc and copper deficiency is also an important topic in medical elementology. 3) MERCURY: Sir Isaac Newton was well known to be distrustful of others in his last years. The clinical picture was characterized by severe neuropathy, which was caused by heavy exposure to mercury during his long scholarly life. Children sometimes break thermometer in their mouth. Does metallic mercury in the thermometer induce mercury intoxication ? The answer is no. Intestinal absorption of metallic mercury is quite low, and thus ingested mercury rarely induces intoxication. The mercury is simply excreted through the feces within a day or two. One should attempt to wash the mercury out from the stomach with water. However, do not treat the child with laxatives, as they can increase the intestinal absorption of mercury, resulting in intoxication. 4) METHYLMERCURY: Severe neuropathy was endemic among fishermen and their families in a particular area of Kyushu Island, Japan. They were found to have eaten a great amount of fish, which were contaminated with organic mercury emitted from a fertilizer producing plant. The disease was later named as Minamata disease. The total number of recognized patients has amounted to 3,000 people, to date. 5) CADMIUM: Cadmium deficiency was recently found to depress the development of baby animals by Anke. This finding suggests that cadmium is not only a harmful element but also an essential element. Itai-Itai disease is characterized as osteomalacia, which is followed by severe renal tubular damage. Patients were comprised largely of elderly women who lived in the Jintsu river basin over a long period, and ingested excess cadmium emitted from a mine, which contaminated the local rice and drinking water. Long-term monkey experiments could not demonstrate osteomalacia by cadmium, however, epidemiological and experimental studies showed that an age-related increase in blood pressure is accelerated by cadmium at low doses, but depressed by cadmium at high doses. 6) LEAD: Lead is a very useful element, but a very harmful element as well. Lead has a potent hematopoietic effect on adults, and also negative psycho-neurological effects on babies. Soil pollution from lead has been discussed in relation to depressed intelligence among children living in U. S. slums. Sometimes residents in rural areas are shot with lead slugs by mistake. Do does lead slugs cause lead intoxication? Usually not. Medication is necessary only when lead slugs injure blood vessels or neurons. Most lead slugs do not induce lead intoxication because the lead slugs are soon covered with granular tissues. 7) CHROMIUM: Chromium is one of the essential trace elements, and is related to glucose tolerance and transmission velocity of peripheral nerves. Adverse effects of excessive chromium are chromium ulcers, perforation of the nasal septum, and lung cancer. 8) ARSENIC: Neutron activation analysis revealed excess amounts of arsenic in the hair of Napoleon. It was then suspected that he was killed with arsenic. Concerning the cause of his death, it was shown that grapes were disinfected with arsenic in those days, and that Napoleon might have consumed excess arsenic from drinking wine. However, the cause of his death remains unsolved. On the other hand, arsenic was used to promote health in Austria. Huge doses of arsenic, lethal for ordinary people, were administered to Austrian youths to assist them in Alpinc hiking. Japanese, especially residents in seashore areas, eat sizable amounts of sea weeds, which contain a huge amount of arsenic. Do they suffer from arsenic intoxication? The answer is no. The chemical form of arsenic in sea weeds is methyl-arsenic, the detoxicated chemical form, which does not revert to the active chemical form of arsenic.

By computerized static posturography with sway frequency analysis, subclinical effects of lead on postural balance was examined in 29 female workers (lead workers) employed at a glass factory for 3-17 (mean 7.9) years in Beijing, China, in relation to brainstem function assessed by brainstem auditory evoked potential (BAEP). Their blood lead concentrations ranged from 26 to 79 (mean 55.7) microg/dl; ages were 21-30 (mean 28) years. Control subjects, aged 22-29 (mean 27.0) years, were 14 healthy female workers at a textile factory located in the same district. With eyes closed, power of the sway of high (2-4 Hz) and low (1 Hz or less) frequencies in lead workers was significantly larger than that in controls; with eyes open, their power of the sway of low frequency was significantly larger (p

Recombinant adeno-associated virus (AAV) has attracted tremendous interest as a promising vector for gene delivery. In this study we have developed an HIV-1 vaccine, using an AAV vector expressing HIV-1 env, tat, and rev genes (AAV-HIV vector). A single injection of the AAV-HIV vector induced strong production of HIV-1-specific serum IgG and fecal secretory IgA antibodies as well as MHC class I-restricted CTL activity in BALB/c mice. The titer of HIV-1-specific serum IgG remained stable for 10 months. When AAV-HIV vector was coadministered with AAV-IL2 vector, the HIV-specific cell-mediated immunity (CMI) was significantly enhanced. Boosting with AAV-HIV vector strongly enhanced the humoral response. Furthermore, the mouse antisera neutralized an HIV-1 homologous strain, and BALB/c mice immunized via the intranasal route with an AAV vector expressing the influenza virus hemagglutinin (HA) gene showed protective immunity against homologous influenza virus challenge. These results demonstrate that AAV-HIV vector immunization may provide a novel and promising HIV vaccination strategy.

In this study, the role of δ-aminolevulinic acid dehydratase (ALAD) variants in lead susceptibility was examined. The study subjects comprised 223 male workers, and the relationship between their blood lead level and erythrocyte ALAD activity or plasma/urine δ-aminole-vulinic acid level was studied. Leukocyte specimens from 11 workers, whose erythrocyte ALAD activities were as low as one-fifth that of the other normal workers, were subjected to analyses of their ALAD 1 and ALAD 2 alleles. Further, the entire exon fragment of the ALAD gene was analyzed by polymerase chain reaction, and the reaction product was used as a target for direct DNA sequencing. Genomic DNA analysis revealed that all 11 workers had the ALAD 1-1 allele, whereas the entire ALAD gene analysis failed to indicate other variants, except for the Rsa I site. The depletion in erythrocyte ALAD activity was not found to be caused by the ALAD 2 allele.

Rats of Long-Evans Cinnamon (LEC) strain were used as a hepatorenal syndrome model of fulminant Wilson's disease. Copper levels in the kidneys increased markedly from 16 to 126 microg Cu/g from 12 to 16 weeks, and remained at the same level at 16 and 19 weeks when the rats suffered from severe renal dysfunction and also at 20 weeks in some other normal rats. The above findings imply that the renal dysfunction may have been induced independently of the copper level in the kidneys. The present study suggested the following mechanism: immediately after copper-induced hepatic dysfunction, plasma copper-metallothionein (CuMT), which was released from the liver, became elevated. The elevation was closely related to the increases in alkaline phosphatase, glucose and amino acids, all in the urine. The above findings suggest that plasma CuMT, which was released from the liver into the blood upon copper-induced hepatic dysfunction, was subsequently filtered at the glomeruli due to its smaller molecular weight, and then caused dysfunction of the brush border membrane of the renal proximal tubules probably after splitting into radical copper and amino acids in acidic vesicles close to the membrane. The critical concentration of plasma CuMT required to induce renal dysfunction was estimated as 1 microg Cu/l.

A fluorometric high-performance liquid chromatographic (HPLC) method was developed for the highly sensitive measurement of delta-aminolevulinic acid (ALA) in biological materials. By using this method, we determined ALA in the plasma and urine of 418 workers occupationally exposed to lead and in the plasma and urine of 227 controls. The concentrations of ALA in the plasma and urine of lead workers were significantly elevated as compared with those of the controls. The concentration of ALA in plasma and urine was highly correlated with that of lead in blood in lead workers. It was found that the correlation (r = 0.742) between log of plasma ALA concentrations and blood lead concentrations in lead workers was similar to that (r = 0.711) between log of urine ALA concentrations and blood lead concentrations. These results demonstrated that the measurement of ALA in plasma or in urine using a fluorometric HPLC method was useful for the biological monitoring of lead workers.

To clarify the effects of lead on autonomic and central nervous system functions, electrocardiographic R-R interval variability (CVRR) as well as visual and brainstem auditory evoked potentials (VEP and BAEP) were measured in 36 female workers exposed to lead (exposed group) and in 15 female textile workers (unexposed group). The C-CVLF, C-CVHF (two component CVs of the CVRR reflecting sympathetic and parasympathetic activities, respectively), and LF/HF ratio (indicator of sympatho-vagal balance) were also computed from component spectral powers by means of autoregressive spectral and component analyses. The exposed group had engaged in glass work for 2-17 (mean 7.8) years. Blood lead (BPb) concentrations were 25.8-79.3 (mean 55.6) micrograms/dl in the exposed group and 4.7-8.6 (mean 6.3) micrograms/dl in the unexposed group. The CVRR, C-CVLF, C-CVHF, and LF/HF ratio in the exposed group were significantly lower than those in the unexposed group. Also, the exposed group had more complaints of subjective symptoms and signs than did the unexposed group. On the other hand, no significant differences in either VEP or BAEP latencies were found between the two groups. It is suggested that autonomic nervous function is more susceptible to lead than visual and auditory nervous functions; lead affects sympathetic activity more strongly than parasympathetic activity.

Critical daily dose of cadmium in residents in cadmium-polluted areas in Japan, were quite diverse by area. Some elucidations for the diversion shall be discussed based on our recent experimental data. 1) Aging aggravated cadmium health effects in rabbits. 2) Excessive dietary zinc and/or copper aggravated cadmium health effects in old animals, but did not in young animals. The effects were quite diverse by age. 3) Low-protein diet was a potent factors aggravating cadmium health effects especially in old rats. 4) It may be difficult, therefore, to estimate a single and unanimous critical daily dose of cadmium, but it is highly recommended for old residents in cadmium-polluted areas, and probably also for old cadmium workers, to avoid excessive exposure to zinc and/or copper, and to take enough protein to avoid aggravating cadmium health effects.

Review of previous experimental and epidemiological studies indicated some relationship of water quality with cardiovascular mortalities and the possible involvement of selenium in cardiomyopathy and of cadmium in hypertension. Present studies on rat models for hypertension, stroke and atherosclerosis revealed significant alterations in plasma and some organ contents of magnesium (Mg) among macroelements and of zinc (Zn) among microelements so far examined, suggestive of the possible involvement of these minerals in hypertension mechanisms, especially in its intracellular processes in addition to causative and preventive roles of macroelements such as sodium (Na), potassium (K) and calcium (Ca) that have been experimentally proven by our previous studies. In our world-wide epidemiological studies on cardiovascular diseases and nutrition, 24 hour urinalysis data of 5 Chinese populations showed not only correlation of Na but also inverse correlations of Ca and Mg with blood pressure. Moreover, comparative analysis on water quality in 6 populations with high and low cardiovascular mortalities has demonstrated Ca and/or Mg contents are obviously higher in those with low risks.

A protein of low molecular weight (MW 12, 000) was detected in the urine of a rabbit given cadmium for 17 months, by polyacrylamide gel electro-phoresis in the presence of sodium dodecyl sulfate. This protein was identified as β2-microglobulin by electrosyneresis using standard β2-microglobulin, a urine sample and anti rabbit β2-microglobulin mouse serum. The urinary concentration of β2-microglobulin in the rabbit fed a diet containing cadmium for 17 months was estimated to be 8-40 mg/l by staining the gel with silver and to be 10-20 mg/l (3.6-7.2 mg/day) by electrosyneresis.

Twelve volunteer students were experimentally exposed to 0, 27, 81 or 201 ppm trichloroethylene for 4 hours, and suffered from irritation to mucous membrane of eyes and throat at over 27 ppm trichloroethylene. No headache or physiological responses were reported at 27 ppm; headache occurred at levels over 81 ppm. Accumulated urinary excretion of total trichloro-compounds, trichloroacetic acid and trichloroethanol for 6 days after trichloroethylene exposure increased linearly with environmental trichloroethylene concentration in volunteers experimentally exposed to 0–315 ppm trichloroethylene.

Natural history of cadmium health effects was studied on monkeys and rabbits given cadmium chloride orally or subcutaneously for a long period: 6 male monkeys were given pelleted food containing 100 micrograms Cd/g over a period of 180 weeks, 15 male rabbits pelleted food containing 300 micrograms Cd/g over a period of 24 weeks, 13 male rabbits daily subcutaneous injections at a dose level of 0.5 mg Cd/kg over a period of 44 weeks, and 23 rabbits subcutaneous injections at a dose level of 0.5 mg Cd/kg 6 times a week over a period of 21 weeks, respectively. Sodium dodecyl polyacrylamide gel electrophoresis and silver staining (detection limit of protein: 80 micrograms/dl) revealed that urinary protein of molecular weight 12,000 (probably beta 2-microglobulin) increased slightly prior to the appearance of proteinuria, glycosuria or aminoaciduria. Remarkable increase in urinary protein of molecular weight 12,000 was observed by Amidoblack 10 B staining (detection limit: 4 mg/dl) around the time when renal dysfunctions appeared. The above result might suggest that the remarkable increase in urinary beta 2-microglobulin is associated with renal dysfunctions, while the slight increase is caused by other mechanisms than renal dysfunctions.

Respiratory elimination of benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol were studied after exposure in human volunteers to those solvents. 1. Solvent concentration in expired air decreased rapidly with time after the cessation of exposure and the decrease was expressed as an equation. Ethyl acetate and ethyl alcohol in expired air decreased faster than did other organic solvents. The decrease was very slow in acetone. 2. Large amounts of retained acetone, benzene and n-hexane were eliminated through the lungs as unchanged solvents, while the amount of eliminated ethyl acetate was almost negligible. 3. The ratio of respiratory elimination to the inhaled (environmental) organic solvent suggested that the determination of respiratory concentration is helpful for estimating environmental benzene, acetone, trichloroethylene and toluene concentration.

An apparent difference in trichloroethylene metabolism was observed between animals; human, rabbit and rat exposed to trichloroethylene. Rats metabolized the substance most rapidly, while metabolism in human proceeded at the slowest rate. The ratio of trichloroethanol to trichloroacetic acid, both the main metabolites in urine, was the largest in rabbit and the smallest in human.There was not observed a significant sex difference in trichloroethylene meta-bolism in rat, while there seemed to exist the age difference in trichloroethylene metabolism in rat though not significant.The metabolic pathway of trichloroethylene in rats did not alter with the size of trichloroethylene intraperitoneally injected at dose levels of 22-368 mg/kg. This might suggest to establish the maximum allowable concentration of trichloroethylene in the working environment from the viewpoints other than the altered metabolic pathway of trichloroethylene with the difference dose level. It was probably due to the physical mechanism that the ratio of total trichloro-compounds in urine to the dose of trichloroethylene decreased with the increase of dose.

Rabbits were fed diets containing 300 ppm cadmium for up to 54 weeks, and signs of cadmium intoxication were studied. The earliest signs of intoxication were amino-aciduria and enzymuria, both of which were detected after 14–16 weeks. Anemia was observed after 27 weeks, and later proteinuria and glycosuria appeared. Loss of body weight and appetite were also seen after 42 weeks of cadmium feeding. Osteomalacia was not observed. The above data suggest that early cadmium intoxication can be detected by determining urinary excretion of amino acids and enzymes. Proteinuria and glycosuria indicate a later stage of cadmium intoxication.

Vitamin D metabolism in primates with chronic exposure to cadmium was studied in relation to Itai-Itai disease. In a series of experiments, crab-eating monkeys were fed cadmium-contaminated rice (1.33 micrograms Cd/g) or a diet containing 3 micrograms/g cadmium chloride for 6 years. These treatments had no effect on the 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 25-hydroxyvitamin D (25(OH)D) in the serum. This is consistent with unchanged production of 1,25(OH)2D and 24,25(OH)2D by renal mitochondria prepared from the same animals. No indication of renal dysfunction was observed. In another series of experiments, rhesus monkeys were fed a diet containing 3, 10, 30, or 100 micrograms/g cadmium for 9 years. Serum vitamin D metabolites and renal production of 24,25(OH)2D also remained unchanged. In contrast, renal 25(OH)D-1-hydroxylase (1-hydroxylase), which is responsible for the production of 1,25(OH)2D, seemed to be suppressed in the animals fed 30 or 100 micrograms/kg cadmium-contaminated diet (no statistical significance). These animals had indications of mild renal dysfunction, and there was a strong negative correlation between 1-hydroxylase and urinary concentration of either protein or beta 2-microglobulin. These data suggest a slight change in the total enzyme activity, possibly due to mild renal dysfunction. Since substrate (25(OH)D) concentration is much lower and thus rate-limiting in vivo as compared with that in vitro assay system used in this study, the slight change of enzyme activity would not have been sufficient to affect the serum level of 1,25(OH)2D. No skeletal abnormality was observed in any of these animals. In view of these data, the length of cadmium exposure and the life span of animals as well as epidemiological data published elsewhere, factors other than cadmium may also be involved in the development of Itai-Itai disease.

Metabolism of trichloroethylene with special reference to the metabolic pathway and rate were studied; trichloroethylene metabolites in urine were determined in rats, which were intraperitoneally administered with trichloroethylene or its metab-olites such as chloral hydrate, trichloroacetic acid or trichloroethanol. One-third of trichloroethylene administered was found to be metabolized to trichloroethanol via chloral hydrate. A minor metabolite, trichloroacetic acid, was suggested to be produced via chloral hydrate or via trichloroethanol.Metabolic rate from trichloroethylene to chloral hydrate was relatively slow, while the biotransformations of chloral hydrate to trichloroethanol and to trichloro-acetic acid were very rapid. The metabolic rate of trichloroethanol to trichloroacetic acid was remarkably slow.Metabolism of trichloroethylene in rabbits was demonstrated as well.

Twenty-one male rabbits were divided into three groups: rabbits of two groups were given pelleted food containing cadmium chloride at a dose level of 300 micrograms Cd/g over periods of 44 or 19 weeks. Rabbits of the last group were given ordinary commercial pelleted food and served as controls. Cadmium increased urinary protein and amino acid by week 19 and increased it to a remarkably high level by week 44. After cessation of cadmium exposure, rabbits of the first group (44 weeks exposure group) showed only little recovery from cadmium health effects: proteinuria and aminoaciduria were slightly improved. Depressed hepatic functions were also slightly improved, but did not return to the control level in 24 weeks. Fat and bone metabolism also remained depressed below the control level. Anemia did not also readily recover. On the other hand, rabbits of the second group (19 weeks exposure) recovered from the effects of cadmium: proteinuria and aminoaciduria in most animals disappeared soon after the end of cadmium exposure, plasma GPT fell after 1 week, and hemoglobin and hematocrit returned to normal in 6-11 weeks. The above results show that after cessation of cadmium exposure, mild cadmium-induced health effects were reversible in a short period, while more severe effects were not readily reversible. High performance liquid chromatographic (HPLC) profiles of renal and hepatic cadmium-thionein (Cd-MT) during and after exposure to cadmium showed no correlation to the degree of cadmium health effects, and therefore, did not help to elucidate mechanisms of the recovery from cadmium-induced health effects, probably because cadmium not bound with metallothionein (non-MT-Cd) is responsible for inducing renal effects.

Mechanisms of respiratory retention of organic solvents are discussed. Respiratory retention, uptake and excretion were estimated separately in 66 men and women volunteer students exposed to benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol. After 2 hrs exposure, respiratory retention reached constant levels; these differed for each of the 7 organic solvents tested. No sex difference in retention was observed. Respiratory excretion values differed as 100 × concentration in expired air immediately following breathing of solvent free air/concentration of solvent in air breathed during exposure. Men excreted more toluene and trichloroethylene than did women. Uptake varied 27–60%.

Three fatal cases of organic solvent abuse revealed high levels of toluene in blood and alveolar air and a high level of hippuric acid, metabolite of toluene, in urine. The lethal concentration of toluene was estimated to be 2,000 ppm.

Thinner sniffing was prevelent among High School Boys in Gunma Prefecture during 1968. Glue was used in some cases which contained a large amount of methyl alcohol and this appeared to be very hazardous to the optic nerves, lungs and bronchi.This prevelence of boys sniffing thinner was discovered to be 3.0% by the determination of urinary hippuric acid, a toluene metabolite.Epidemiology of thinner sniffing was the same as that of smoking, and the control of smoking would reveal the decrease of smoking as well as the decrease of thinner sniffing. The source of control should be at the Senior High School age level. One effective means of control was that parents be trustworthy and reliable in their actions. The daily lives and associated friendships of the children should be well supervised. Well informed teachers and participation in sports was found not to be helpful in exercising control in these fields.

Retention and respiratory elimination of trichloroethylene, and urinary excretion of trichloroethylene metabolites were determined in ten volunteer students exposed to 250–380 ppm trichloroethylene for 160 min. 1. Retention amounted to 36% of the inhaled trichloroethylene. 2. Trichloroethylene was eliminated through respiration after exposure, and the concentration in expired air decreased exponentially with a rate constant k∶:0.14 hour−1. Respiratory elimination of trichloroethylene was 16% of the retained trichloroethylene. 3. Urinary excretion of total trichloro-compounds decreased exponentially with k∶:0.23 day−1 in males and 0.20 in females. 4. Urinary excretion of trichloroacetic acid and trichloroethanol were 32.6% and 48.6% in males, and 43.9% and 42.7% of the retained trichloroethylene in females. 5. Trichloroacetic acid in females was found to be 2–3 times more than that in males for the first 24 hours after exposure. Trichloroethanol, on the contrary, was excreted twice more in males than in females for the first 12 hours. Therefore, the trichloroethanol to trichloroacetic acid ratio was significantly different between males and females by 5.5 times for the first 24 hours after exposure. 6. These findings suggest a sex difference in human metabolism of trichloroethylene. Urinary total trichloro-compounds form a better index of trichloroethylene exposure than urinary trichloroacetic acid.

The levels of copper and ceruloplasmin in the cerebrospinal fluid (CSF) of patients with Wilson disease were investigated. Ceruloplasmin concentrations in the CSF of all patients were almost the same but were lower than those of the controls. CSF copper concentrations in patients without neurologic signs were within the normal range, 22 +/- 6 ng/ml. In contrast, CSF copper concentrations in patients with neurologic signs (69-98 ng/ml) were significantly higher than the normal levels before and at the beginning of the treatment with D-penicillamine; it gradually decreased in response to treatment. These results suggest that the appearance of neurologic manifestations in Wilson disease is not related to the CSF ceruloplasmin concentration. The CSF copper concentration in this disease appears to reflect copper accumulation in the brain and may be useful as a marker for monitoring therapy.

Sodium dodecyl sulfate (SDS) acrylamide gel electrophoretic studies were performed on low-molecular-weight (LMW) proteins in urine from rabbits given sub-cuteneous injections of cadmium chloride at a dose level of 0.5mgCd/kg over a period of 42 weeks to evaluate the procedure for screening early effects of cadmium : in the 1st week, a gradual increase in urine cadmium was found ; in the 3rd week, slight LMW proteinuria (proteins of MW 12, 000 and 25, 000); in the 6th week, slight protein-uria, (proteins mostly of MW 67, 000); in the llth-13th week, aminoaciduria, glycos-uria, proteinuria and LMW proteinuria (proteins of MW 12, 000 and 25, 000). As shown above, protein of MW 12, 000 (probably β2-microglobulin) and 25, 000 (pro-bably retinol-binding protein) increased in urine a little earlier than protein of MW 67, 000 (probably albumin) in rabbits given cadmium. Therefore, urine LMW pro-teins were thought to be effective indices for screening early effects of cadmium.Sixty-80% of proteins in urine from rabbits given cadmium were proteins of MW 67, 000, while only 10% were LMW proteins. This fact might suggest that cadmium affect tubules as well as glomerules.

(1978). Gas-liquid chromatographic determination of trichloroethylene metabolites in urine. American Industrial Hygiene Association Journal: Vol. 39, No. 6, pp. 506-510.

The present study re-evaluates five funcional tests for measuring fatigue. These include tapping, colour calling, knee reflex, flicker and two-point discrimination tests. Eight faculty staff and technicians of a medical school were tested in the morning of each working day over a period of four years.A period of accustomization to the tests was observed. In the first 5 to 10 days of testing scores fluctuated widely; thereafter most test scores remained relatively constant for each individual. However the tapping and colour calling tests required up to one and a half years to become reproducible.Among subjects there were large variations in the result of the knee reflex and two-point discrimination tests, and relatively small variations for the tapping and flicker tests. In all five tests however intra-personal were significantly less than inter-personal variations.No age-trend was observed among the subjects, whose ages ranged only from 20 to 40 years.The female subjects performed the colour calling test faster than the males.No seasonal pattern was observed. The only weekly pattern was a significantly greater coefficient of variation of the flicker test scores for Thursday and Friday. The menstrual cycle did not appear to affect any of the fatigue test performances.For individuals accustomed to these tests difference between pre- and post-stress performance may be a reproducible measure of fatigue.

UrinaryΒ2-microglobulin (MG) was determined in 99 elderly people above 50 years of age from an area with no known cadmium pollution. With advancing age, the urinary MG increased as well as the urinary protein, urinary retinol-binding protein (RBP), and plasma urea nitrogen. Nevertheless, age effects were not observed in renal functions such as creatinine clearance or tubular reabsorption of phosphorus. Analysis of the relationship between urinary MG and parameters of the renal functions suggested 2-step increases in urinary MG: a slight increase between 160 and 1600Μg/L and a remarkable increase above 1600Μg/L. The latter strong increase in urinary MG was closely related with depressed tubular reabsorption of MG, but was independent of tubular reabsorption of phosphorus. The screening level of urinary MG for renal tubular dysfunction is suggested at 1600Μg/L.

Ten male rhesus monkeys, each weighing 3.5 kg, were divided into four groups of 3, 3, 2, and 2, and were fed daily with 100 g pelleted food containing 300, 30, 3, and 0 ppm cadmium, respectively. Urine samples were collected every 2 weeks and blood samples every 4 weeks. One monkey each of the 300 and 30 ppm groups was autopsied for pathological examination and tissue cadmium determination at the week 24 of the experiment; the remaining 8 animals were killed after 55 weeks. The lowest exposed group (3 ppm) did not show any specific biological response to cadmium over a period of 55 weeks. In the 30 ppm group, no significant changes were observed for up to 24 weeks, although cadmium concentration in the renal cortex and urine at 24 weeks were 300 mug/g wet weight and 18 mug/l., respectively. Plasma urea nitrogen and urine protein (quantitative determination) increased after 30 and 36 weeks. At 55 weeks of the experiment, qualitative tests were negative for low molecular weight proteinuria and glycosuria, and the results remained normal for renal and liver function tests and blood analysis, although cadmium concentrations in the renal cortex of two monkeys were 460 and 730 mug/g wet weight and those in the liver were 110 and 160 mug/g wet weight, respectively. In the highest exposure group (300 ppm), urine cadmium increased to 250 mug/l. by 11 weeks, and urine retinol-binding protein, plasma GOT, GPT, and LDH increased after 12 weeks. Proteinuria (quantitative determination), glycosuria, aminoaciduria (panaminoaciduria), and erythrocytopenia were observed after 16 weeks, when urine cadmium was 500-900 mug/l. Hypohemoglobinopathy and proteinuria (qualitative determination) were observed after 20 and 24 weeks, while cadmium concentrations in the renal cortex and the liver were 760 and 430 mug/g wet weight at 24 weeks, respectively. Slightly depressed tubular reabsorption of phosphate, increased urine beta(2)-microglobulin, increased plasma urea nitrogen, and increased plasma alpha(2)-globulin fraction (electrophoresis) were observed between 28 and 30 weeks of the experiment. Creatinine clearance and plasma cholinesterase decreased after 47 and 54 weeks, respectively. Cadmium concentrations in the renal cortex and the liver of two monkeys at 55 weeks were 350 and 580 mug/g wet weight and 410 and 630 mug/g wet weight, respectively. Pathological examinations revealed denaturation, destruction, and regeneration of the epithelial cells in renal proximal tubules, but no pathological changes in osseous tissues. Critical cadmium concentration in the renal cortex was estimated to be 380 mug/g wet weight for low molecular weight proteinuria and 470 mug/g wet weight for proteinuria, glycosuria, and aminoaciduria. Critical concentration in the liver was also estimated to be 210 mug/g wet weight. The apparent biological half-time of cadmium in monkeys at autopsied stage was calculated to be 0.66, 6.4, 5.2, and 22.4 years for the 300, 30, 3, and 0 ppm groups, respectively.

The urinaryΒ 2-microglobulin (MG) of 236 inhabitants of three cadmium-polluted areas was studied in relation to urinary cadmium, an index of cadmium exposure. The urinary MG was elevated with urinary cadmium and with age, except in the Fuchu district, where the urinary MG remained remarkably high regardless of the urinary cadmium and age. Multiple regression analysis revealed that the district factor was the most potent for elevating the urinary MG, and the age factor was the second most potent. Urinary cadmium was found to be a relatively small factor for elevating the urinary MG.

Two hundred and thirty one urine and 20 blood samples of Japanese subjects from 4 geographic areas without known chromium pollution were assayed for chromium by direct flameless atomic absorption spectrophotometry. Normal chromium level in urine of Japanese subjects was 0.41 microg/L on an average. Urine level was less than 0.8 microg/L for all age and sex groups. Chromium levels in 2 hour urines did not correlate with those in 24 hours urine. Blood level of chromium was 2.9 ng/mL. A rabbit given an oral administration of 100 mg hexavalent chromium excreted 8.2 mg in 15 days after administration. No hexavalent chromium could be detected in urine. Ninety percent of the urinary excretion occurred within 2 days of administration.

Male and female mice of the RF and ICR strains at various ages were given methylmercury chloride orally at a dose level of 30 mg Hg/kg, and the accumulated rates of death were compared. Higher accumulation rates of death were observed as follows: greater in RF strain mice than in ICR strain mice, in male mice than in female mice, and in aged mice than in young mice. The mechanisms of age and sex difference in methylmercury toxicity were not clarified by the determination of total mercury and methylmercury in the brains. The accumulated rates of death after a single oral methylmercury administration at a dose level of 30 mg Hg/kg were also compared among three groups of mice, which were previously acclimatized to an environmental temperature of 8, 22, or 38°C. The highest toxicity was found when the environmental temperature was 8°C, followed by those at 22 and 38°C. The mechanism of the aggravating effects of low environmental temperature in methylmercury toxicity was studied in relation to the critical concentration. The toxicity of methylmercury was attenuated by keeping animals warm by putting them on a warming mat or placing them in a room with higher environmental temperature.

Retinol-binding protein (RBP) in the Rhesus monkey had the same electrophoretic mobility, molecular weight, and common antigens as human RBP; beta 2-microglobulin protein (MG) had similar electrophoretic mobility and partial common antigens to human MG. After a prolonged oral administration of cadmium chloride to 10 monkeys over a period of 55 weeks, one monkey of the 30 mg Cd/day group indicated RBPuria and MGuria with the use of anti-human RBP and MG sera when proteinuria appeared. The immunological assay of low-molecular-weight proteins in urine was not applicable for the early detection of cadmium health effects in monkeys.

In recent years it has been suggested in Japan that occupational trichloroethylene exposure will induce primary pneumatosis cystoides intestinalis coli. A series of two experiments were conducted to ascertain the cause-effect relationship between trichloroethylene and pneumatosis as follows: In the first experiment, 12 male rats of Fischer strain were exposed to trichloroethylene at a nearly lethal concentration for 12 wk. Five out of 12 rats died during the experiment, and body weight gain was extremely depressed. However, neither pneumatosis nor histological changes were observed. No changes were observed in 4 control rats as well. In the second experiment, 38 male rats of Sprague-Dawley strain were exposed to 800, 200 or 50 ppm trichloroethylene over a period of 12 wk. Two out of 13 rats of the 800 ppm group died, and body weight gain was suppressed. Mild suppression in body weight gain was also observed in the 200 ppm group. However, pneumatosis was not observed in any rats of trichloroethylene groups. No pathological changes were observed in 13 rats of the control group. The foregoing results suggest that trichloroethylene cannot induce pneumatosis cystoides intestinalis in rats of these two strains. Inasmuch as rats are not prone to develop pneumatosis, the possibility for trichloroethylene to induce this disease in man cannot be denied.