An Experimental Study on Depigmenting Activity of 4-(p-Hydroxyphenyl)-2-Butanone in C57 Black Mice: Depigmenting Activity of HPB in Black Mice: Yoshiharu FUKUDA, et al. Department of Public Health, Kumamoto University School of Medicine-The authors previously reported three. cases of occupational leukoderma in workers engaged in a 4-(p-hydroxyphenyl)-2-butanone (HPB. Raspberry Ketone) manufacturing process. These cases suggested that HPB might be a chemical causing the leukoderma and it had depigmenting activity. The purpose of this study is to evaluate the depigmenting activity of HPB by using laboratory animals. HPB, its two crude products and monomethyl ether of hydroquinone as the positive control were topically applied to the dorsal surface of C57 black mice. Depigmentation was shown in black mice to which HPB and its crude products were topically applied but the effect produced by these chemicals was weaker than that seen with monomethyl ether of hydroquinone. Though evidence of a reduction in melanocytes and pigmentation was not documented in the microscopic analysis, spectrophotometric assay showed a decrease in melanin content in the hair of mice to which HPB and the crude product had been applied. The results indicated a depigmenting activity of HPB and supported the conclusion that the leukoderma which we reported in a companion paper was induced by exposure to HPB and/or its crude products. Nevertheless, the potential of this depigmenting activity is so weak that the development of leukoderma due to these chemicals may be limited to those who are occupationall ex osed.

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Real Dysfunction Indicators in Lead Exposed Workers: Kap-Yeol JUNG, et al. Department of Preventive Medicine and Industrial Medicine Research Institute, Dong-A University School of Medicine—This study was undertaken to find out which indicators were most valuable as markers of renal dysfunction related to lead exposure. We selected 75 male workers from the secondary lead smelter, plastic stabilizer and radiator manufacturing industries (the “exposed” group) and 64 male office workers (the “control” group). Blood lead, blood zinc protoporphyrin, urine lead, urine coproporphyrin, δ-aminolevulinic acid dehydratase activity, and urine δ-aminolevulinic acid were chosen as indicators of lead exposure. Blood urea nitrogen, serum creatinine, serum uric acid, urine N-acetyl-β-D-lucosaminidase, urine albumin, urine α₁-microglobulin and urine β₂-microglobulin were used as indicators of renal dysfunction. The urine α₁-microglobulin level was significantly associated with the lead exposure level. Blood urea nitrogen, urine N-acetyl-β-D-glucosaminidase and urine al-microglobulin levels were highly correlated with indicators of lead exposure. Urine α₁-microglobulin had the highest correlation with other indicators of renal function. Conclusively, blood urea nitrogen, urine N-acetyl-β-D-glucosaminidase and urine α₁-microglobulin are useful indicators, but urine α₁-microglobulin is the earliest and the most valuable indicator of renal dysfunction due to lead exposure.

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Use of Kinetic and Mechanistic Data in Species Extrapolation of Bioactivation: Cytochrome P-450 Dependent Trichloroethylene Metabolism at Occupationally Relevant Concentrations: John C. LlPSOCOMB, et al. United States Air Force, Armstrong Laboratory. Toxicology Division-Trichloroethylene (TRl) is an industrial solvent and environmental contaminant; therefore exposure to TRl occurs in diverse human populations. TRl causes hepatocellular carcinoma in B6C3F1 mice, but not rats; this suggests that TRI may be metabolized differently in the two species. We investigated the metabolism of TRl and the eftect of TRl on enzymatic activities indicative of specific cytochrome P450 (CYP) forms in hepatic microsomes from mice, rats and humans. Studies in microsomes estimated Michaelis-Menten kinetic parameters by saturation analysis. K_m values were 35.4, 55.5 and 24.6 pM and V_max values were 5, 425, 4, 826 and 1, 440 pmol/min/mg in pooled mouse, rat and human microsomes, respectively. TRl (1, OOO ppm) inhibited CYP2E1 dependent activity in all three species and BROD activity in mice and rats; TRl (1, OOO ppm) increased CYP1A1/1A2 activity, and had no effect on CYP2A activity. Inhibition studies with mouse hepatic microsomes demonstrated that TRl was a competitive inhibitor of CYP2E1, with Kj Of 50 ppm. TRl noncompetitively inhibited CYP2B-dependent activities in the rat and mouse. Preincubation of microsomes with TRl and NADPH decreased the absorbence of CO-bound CYP in all three species, but the dose-dependence was most evident in mouse hepatic microsomes. These results have quantified the interspecies difference in CYP-dependent TRl bioactivation and indicate that under both equivalent and occupationally relevant (hepatic) exposure conditions the human is at less risk of forming toxic CYP-derived TRl metabolites.

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Occupational Leukoderma in Workers Engaged in 4-(p-Hydroxyphenyl)-2-Butanone Manufacturing: Yoshiharu FUKUDA, et al. Department of Public Health, Kumamoto University School of Medicine-Occupational leukoderma was found to be caused by exposure to depigmentation agents. This is the first report associated with the depigmenting activity of 4-(p-hydroxyphenyl)-2-butanone and its crude products. The purpose of this paper is to present three cases of occupational leukoderma in the upper extremities of workers engaged in the manufacturing of 4-(p-hydroxyphenyl)-2-butanone. Two workers had symptoms of dermatitis in the same areas before depigmentation. An epidemiological study, their clinical courses and results of phototesting suggest that these cases of leukoderma were due to exposure to 4-(p-hydroxyphenyl)-2-butanone and its crude products.

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Prolonged Exposure to Industrial Noise: Cochlear Pathology does not Correlate with the Degree of Permanent Threshold Shift, but is Related to Duration of Exposure: Mariola SLIWINSKA-KOWALSKA, et al. Department of Physical Hazards, The Nofer Institute of Occupational Medicine-It has been shown that the damaging effects of noise on the mammalian inner ear strongly depend upon parameters of exposure, such as the intensity of noise, the duration of exposure, etc., but the relationship between permanent hearing loss and cochlear damage still remains unclear. In this study, we were interested in the damaging effects of exposure to typical steady-state, wide-band industrial noise acting for as long as 12 weeks on guinea pigs. The aim of the study was to evaluate the relationships among the duration of exposure to industrial noise, the level of permanent hearing loss and the degree of cochlear injury and to assess the possible mechanisms of industrial noise-induced hearing loss. The results of the study indicate that 1) prolonged exposure to industrial noise causes in guinea pigs a relatively fast increase in permanent hearing threshold shift (PTS) up to 30 dB, which reaches the asymptotic level after 4 weeks of exposure; 2) the first 30 dB of PTS is caused almost exclusively by the damage to outer hair cells; 3) the degree of cochlear damage is not related to the level of permanent threshold shift; 4) the progression in cochlear pathology depends upon the duration of exposure; 5) both micromechanical and metabolic mechanisms seem to be involved in the development of industrial noise-induced hearing loss.

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Equilibrated Vapor Concentrations for Bicomponent Organic Solvents: Hajime HORI, et al. Department of Environmental Management I, School of Health Sciences, University of Occupational and Environmental Health, Japan-The equilibrated vapor concentrations for bicomponent organic solvents of toluene-o-xylene, methanoltoluene and methanol-o-xylene mixtures were measured at various compositions. The equilibrated vapor concentration of each component for the toluene-o-xylene system was almost proportional to its liquid phase molar fraction. For the methanoltoluene and the methanol-o-xylene systems, however, methanol vapor occupied 80-90% of the total organic vapor in the gas phase, even the molar fraction of methanol in the liquid phase was less than 5%. For the toluene-o-xylene system, because the solution was regarded as an ideal solution, the equilibrated vapor concentrations could be estimated from the saturated vapor concentrations of pure solvents and their liquid molar fractions. On the other hand, the methanoltoluene and the methanol-o-xylene systems could not be regarded as ideal solutions. For these systems, the equilibrated vapor concentrations could be estimated by introducing the activity coefficients calculated with the Margules equation.

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In Vitro Studies on the Depigmenting Activity of 4-(p-Hydroxyphenyl)-2-Butanone: Yoshiharu FUKUDA, et al. Department of Public Health, Kumamoto University School of Medicine-The aim of this study is to investigate the enzymatic properties and the depigmenting activity of 4-(p-hydroxyphenyl)-2-butanone (HPB) in vitro. The activity of HPB as a substrate of tyrosinase, its effect on tyrosinase enzymatic reactions, and its inhibition of the growth and the melanogenesis of cultured melanoma cells were examined. The HPB-tyrosinase reaction and the effect of HPB on tyrosine-tyrosinase and dopa-tyrosinase reactions were followed spectrophotometrically. Fifty percent growih inhibition concentrations (IC₅₀) of several chemicals for melanoma cells and non-pigmented cells were measured. Melanogenic activities in HPB-treated melanoma cells were assayed. The results showed that HPB was oxidized by tyrosinase and stimulated tyrosinetyrosinase and dopa-tyrosinase reactions. The IC₅₀ of HPB for melanoma cells was higher than those of the established depigmenting agents but it was lower than that of HPB for non-melanotic cells. Tyrosine hydroxylase in HPB-treated melanoma cells was stimulated comparecl with the control, but melanin product in HPB-treated cells was almost similar to the control. The results showed that HPB acts as a good substrate for tyrosinase and it stimulates tyrosinase enzymatic reactions, but it inhibits pigmented cell growih selectively. This study suggests that HPB-induced depigmentation is due to a selective cytotoxic effect on pigmented cells rather than to the inhibition to melanogenesis.

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Immune Response in Guinea Pigs Injeoted with Insoluble Beryllium Compounds: Tsutomu YOSHIDA, et al. Department of Public Health, Fujita Health University School of Medicine-The changes in immune response of guinea pigs intrapleurally injected once with beryllium oxide (BeO) or beryllium copper alloy (Be-Cu) were examined. To evaluate the changes in immune response of guinea pigs, two indicators, beryllium lymphocyte transformation test (Be-LTT) and complement hemolyiic activity (CH₅₀), were used. The BeO or Be-Cu injection groups was divided three groups, a high concentration injection group (36 μg Be dose), a low concentration injection group (3.6 μg Be dose) and the control group. The Be-LTT and CH₅₀ were determined in the blood of guinea pigs at 4, 8 and 16 weeks after Be administration. The Be-LTT value at the 4th week in the BeO groups (a high or low concentration injection group, respectively) showed a statistically significant increase (p<0.01) compared with that of the control. In the Be-LTT value for BeO at 8 and 16 weeks after Be injection and the Be-Cu groups, there were no statistical difference between the Be administration groups and the control. On the other hand, only the CH₅₀ of the high concentration group at the 8th week in the BeO injection group was significantly decreased (p<0.01) compared with that of the control. In the other Be injection group, no significant changes in the CH₅₀ was observed compared with the control group. On the basis of the results observed in the present study, there may be a slight difference in the effect on the immune response of guinea pigs caused by BeO or Be-Cu administration. The immunotoxicity of Be in guinea pigs may manifest itself more intensely in the cellular immune response than in the humoral immune response.

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Electrophysiological and Biochemical Effects of Exposure to 2, 5-Hexanedione on Peripheral Nerve in Experimental Diabetic Rats: Takashi KIMURA, et al. Department of Public Health and Hygiene, Oita Medical University-Both 2, 5-hexanedione (2, 5-HD) and diabetes mellitus (DM) cause peripheral neuropathy. Workers with asymptomatic DM could possibly be exposed to n-hexane converted to 2, 5-HD in liver. To clarify 2, 5-HD influences on peripheral nerves in DM, electrophysiological and biochemical changes in DM rats were compared in 2, 5-HD treated and untreated groups. Four groups of rats were studied: the Control group consisted of non-diabetic rats treated with a placebo; the HD group, of non-diabetic rats treated with 2, 5-HD; the DM group, of diabetic rats treated with a placebo; the DM+HD group, of diabetic rats treated with 2, 5-HD. 2, 5-HD was administered at 100 mg/kg/day, five days a week for 8 weeks. The motor nerve conduction velocity (MCV) and motor distal latency (DL) in the rat's tails and glucose, fructose, sorbitol and myoinositol levels in the sciatic nerves were measured. The MCV in the DM+HD group was significantly reduced from the 4th week compared with those in the other groups. 2, 5-HD had no influence on the levels of glucose, fructose, sorbitol and myo-inositol in either the diabetic or non-diabetic group. These results indicated that exposure to 2, 5-HD hastened the onset of peripheral neuropathy in experimental diabetic rats. This study indicates that 2, 5-HD in combination with DM enhances the neurotoxicity. But the mechanisms of the neurotoxic interactions between 2, 5-HD and DM are still unknown. It can be hypothesized that workers with hyperglycemia can suffer from neuropathy due to exposure to n-hexane earlier than those without hyperglycemia.

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A SAS Program for the Stratified Analysis of Follow-Up Data:Yasushi HONDA, et al. Environmental Health Sciences Division, National Institute for Environmental Studies-Mantel-Haenszel (M-H) estimators are robust measures of association for the stratified analysis of epidemiologic studies. This paper describes a SAS macro developed to compute the M-H rate ratio (RR) for a binary exposure and its confidence interval from follow-up data. The program accommodates a virtually unlimited number of stratification factors, allows setting the confidence level, and can easily be applied to the analysis of multi-level categorical exposure variables. Printed output includes stratum-specific rates and RRS and summary M-H RRS and confidence intervals. Summary measures of association are meaningful only if effects are homogeneous across strata. The printed output of the program allows inspection of stratum-specific rate ratios to check this important assumption.

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Recent State and Future Scope of Occupational Health in Japan: Toshiteru OKUBO. Occupational Health Training Center, University of Occupational and Environmental Health, Japan-The most significant characteristic of the working population of Japan is aging. The increase in the senior population puts substantial pressure on the health insurance and pension systems and many health insurance organizations have decided to cut down voluntary programs on occupational health. The nature of occupational diseases has changed from health impairments caused by a single prominent occupational factor to unspecific health problems caused by the combined effect of both occupational and nonoccupational factors. Diseases occurring through this mechanism are called work-related diseases, in contrast to typical occupational diseases. It is no longer eftective to simply remove a single hazardous environmental factor, as has been the major approach in occupational health. A comprehensive approach is more important than ever. Health promotion in the work place is therefore one of the most important services in Japan. Along with the improvement of the work environment, workers'' values regarding labor have also changed and they seek working conditions better than the threshold level to prevent health hazards11). Under these conditions the basic concept of occupational health should not be limited to only minimizing the minus health effects, but it should introduce the idea of seeking positive health. Positive health always seeks to improve health from any level, but up to now medical science has paid very little attention to positive health and there is lack of knowledge and experience. The highest priority of research in this field is therefore to be found in the development of positive health indicators.

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