The recent studies of Itai-itai disease (IID) which have been mainly conducted since 1980 is reviewed. Fifty-one patients were officially designated as having IID from 1980 to 1996. The latest patient registered in 1994 complained of having a bone pain at the age of 72 in 1991. This fact indicates the occurrence of new cases of IID even today. In 75 autopsy cases of IID (1979-1991), Looser zones, which are characteristic of osteomalacia, were observed in 45 (60%). A large number of Looser zones were found in the ribs (356), femur (44), ulna (12), pubic ramus (9) and other bones. The most conspicuous feature of bone histopathology was a marked osteoid accumulation accompanied by the reduction of a bone mass. Loss of bone evaluated by densitometry was related to the severity of renal tubular dysfunction. The renal lesion of IID is characterized by tubulointerstitial nephropathy, and the grade of atrophic changes in tubules in the renal cortex correlates quantitatively with a decrease in kidney weight. The renal function assessed by long-term observation of serum creatinine showed a sustained reduction. Anemia and hypocalcemia, found in the end-stage of IID, were closely associated with an impaired renal function. Extensive measurements of heavy metals in the organs derived from the autopsy cases of IID have shown significantly lower values of Cd, Zn, and Cu in the kindneys, whereas significantly higher values of Cd and Zn were found in the liver, pancreas, thyroid and other organs compared to the control group. It can be inferred that the kidneys of those with IID once had high concentrations of Cd which had been excreted into the urine, associated with the ablation of tubular epithelium. On the based of these findings, the pathogenesis of IID is discussed.

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We have already reported the effect of several carbonyl compounds such as alkanals, 2-alkenals, glyoxals and malondialdehyde, which are formed from oxidized lipids, on the leakage of hepatic enzymes from primary cultured rat hepatocytes. In the case of 2-alkenals, the leakage of lactate dehydrogenase (LDH) took place in a dose-dependent manner and the hepatotoxicity was inhibited by the addition of ascorbic acid and glutathione. In this paper, we investigated the effects of P450-inducers on the hepatotoxicity of 2-hexenal, since the hepatotoxicity of 0.5 mM 2-hexenal against untreated hepatocytes was reduced to 36.7% and 46.3% by the addition of 10μM cimetidine and 1μM α-naphthoflavone, respectively. 3-Methylcholanthrene (MC), phenobarbital (PB), β-naphthoflavone (NF) and dexamethasone (DEX) were used as P450-inducers. In the treatment with 0.5 mM 2-hexenal, the LDH leakage of 3-MC induced hepatocytes was enhanced to 1.4-fold that of non-induced hepatocytes. In the 3-MC induced hepatocytes, the hepatotoxicity of 0.5 mM 2-hexenal was reduced to 38% with α-NF (0.1 μM). Therefore, it is suggested that 2-hexenal is metabolized to hepatotoxic substances by microsomal CYP 1A2 species.

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The metabolism, elimination, distribution and accumulation of N, N'-dimonomethylphenyl-p-phenylenediamine (DMPD), a rubber antioxidant/antiozonant, were investigated in male and female Fischer 344 (F344) rats in a feeding study at three dose levels of 0.004, 0.02 and 0.1% for 2 years. Two isomers were contained in DMPD as major ingredients which were different in methyl group positions. DMPD and its metabolite in the biological fluids and tissues were determined by GC-MS in the selected ion monitoring-mode. Chronic administration of DMPD resulted in its progressive accumulation in adipose tissues (mesenteric, perirenal, epididymal, and ovarial fat). The ratio of the accumulated amount to the ingested dose (the intake of DMPD in a day) was the highest (1570% in male and 2560% in female) in the 0.02% diet group, suggesting the highest accumulation ratio of DMPD in the adipose tissues during 18 to 24 months. The principal route of excretion was through the feces, with small amounts found in urine. When the amounts of excretion were converted to the ingested dose%, about 10-65% of the ingested dose in male and 30-130% in female rats were progressively excreted into the feces after 24 months. The excretion of a hydroxylated metabolite (the presumed oxidation of a methyl group of DMPD) appeared around 1-2 months and was still found at 6 months in feces. The major metabolite in urine was the hydroxylated compound. On the other hand, the accumulation of DMPD in the adipose tissues was extremely reduced in the one-month withdrawal experiment, but the excretion rates of DMPD from epididymal fat in the 0.02 and 0.1% DMPD treated groups were slower than that in the 0.004% treated group. The blood concentrations of DMPD in the 0.004% and 0.02% withdrawal male rats were higher than those of the treated rat groups.

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Radioactivity of ¹³⁷Cs and ⁴⁰K was determined on commercially available products of Houttuynia Herb which were imported from China and Taiwan or processed in Japan, and of Houttuynia cordata harvested in 15 places in Japan and the surrounding soil. On Houttuynia Herb, the concentrations of ¹³⁷Cs and ⁴⁰K were LTD (less than detectable)-7.6 Bq/kg dry and 743-1964 Bq/kg dry, respectively, suggesting that the concentration of ¹³⁷Cs was less than 1% of that of ⁴⁰K. The domestic products were found to contain higher concentrations of ¹³⁷Cs and ⁴⁰K than the imported ones. The concentration of ¹³⁷Cs of Houttuynia cordata harvested in Japan ranged from 0.8 Bq/kg dry to 172 Bq/kg dry, while the concentration of ⁴⁰K was almost the same as that of the commercial products. The concentration ratio of ⁴⁰K in Houttuynia cordata to that in the soil was correlated with the moisture content and the ignition loss of the soil. However, the concentration ratio of ¹³⁷Cs did not show a very clear correlation. When 15 g of Houttuynia Herb or Houttuynia cordata was daily decocted and given for 1 year the former showed the committed dose equivalent of 0.02-0.5 μSv and the latter 0.06-12 μSv. Both of these values were less than 0.5% of the annual effective dose equivalent from the nature, 2.4 mSv.

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o-Phenylenediamine (o-PD), m-phenylenediamine (m-PD), 2, 4-diaminotoluene (DAT) or 2, 4-diaminoanisole (DAA) in aqueous solutions were oxidized with ozone at pH 10.7, and the ozonized solutions were tested for their mutagenicity in Salmonella typhimurium TA 98 in the presence or absence of a mammalian metabolic activation system (S 9 mix). The mutagenicity of m-PD and DAA aqueous solutions with S 9 mix was markedly enhanced by oxidation with 1-to 4-fold mol of ozone, but vanished with sufficient ozonation. An aqueous solution of m-PD and DAA was ozonized at pH 4.0, 7.0 and 10.7, and the mutagenicity of the ozonized solution and extract with ethyl acetate (AcOEt) was tested in S. typhimurium TA 98 with S 9 mix. At all pH values of the solution, mutagenicity was markedly enhanced by ozonation, and that of the AcOEt extract was equal to or greater than that of the aqueous solution. Aminophenazines were observed in the AcOEt extract from the ozonized solution of m-PD and DAA. The contribution of the aminophenazines to mutagenicity, however, was low, and it is suggested that other major mutagenic compounds were formed.

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The analytical method using GC-MS was developed to determine simultaneously eleven chemicals, such as pyrethroid pesticides (empenthrin, allethrin, tetramethrin, resmethrin, phenothrin and permethrin), synergists (1, 1-oxybis (2, 3, 3, 3-tetrachloropropane) (S-421), diethyl phtalate and piperonyl butoxide), a repellent (N, N-diethyl-m-toluamide (DEET)) and dibutyl phthalate, in moth/mite-proofed household products. The eleven chemicals were extracted from the moth-proofing agents and covers for fabric, the moth/mite-proofing sheets and other related products by ultrasonification in acetone for 30 min. The recoveries of the 10 chemicals, except dibutyl phthalate, were found in the mite-proofed paper bag for a vacuum cleaner were 100-103% on the average. The concentration of pyrethroid pesticides which were detected in 42 brands of various household products ranged 0.46-357 mg/g for empenthrin, 0.39-11.8 mg/g for allethrin, 0.24-2.94 mg/g for tetramethrin, 0.11-110 mg/g for permethrin, and 4.47 mg/g for phenothrin, respectively. S-421 and piperonyl butoxide, synergists, ranged 0.06-37.9 mg/g, and 0.06-6.99 mg/g, respectively. The mutagenic responses of the acetone solutions extracted from the household products and S-421 standards ranged from 2.1 to 6.6 revertants (rev.)/mg and 215 rev./mg, respectively. The contribution of S-421 to the mutagenicity of the product extracts was estimated to be from 17.8 to 74.7%.

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We analyzed the CYP2D6 and CYP2C19 genotypes from 5 patients with a diagnosis of subacute myelo-optico-neuropathy (SMON) after the informed consent was obtained. No homozygous poor metabolizer (PM) genotype reported to be associated with Parkinson's disease (PD) was found in the present cases. The mutation located at the Hha I site of the CYP2D6 speculated to be associated with PD was found heterozygously in only one case. As for CYP2C19, no mutant homozygous genotype which was reported to be associated with the low metabolism of mephenytoin was found. And a mutant ml allele was found heterozygously in two cases, and a mutant m2 allele in the one case. There was no significant relationship between SMON and these polymorphisms of CYP2D6 and CYP2C19. These results suggest that the poor metabolizer/extensive metabolizer (PM/EM) polymorphisms of CYP2D6 and CYP2C19 may not be useful molecular markers for predicting the onset of SMON.

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