Fumio Kishida

A quantitative structure-Activity relationship study of the skin irritation potential of phenols.

Quantitative structure-activity relationships (QSARs) for skin irritation potential were studied using twenty-four phenols. Based on the hypothesis that skin irritation is induced by reaction of phenols with macromolecules present in epidermal and dermal levels of the skin, the following descriptors for QSAR were selected, the absolute hardness (N) calculated from HOMO (the highest occupied molecular orbital) and LUMO (the lowest unoccupied molecular orbital) energy levels for reactivity, and logP (octanol-water partition coefficient) for permeability. Using these descriptors, we fitted a regression function to the set of skin irritation scores obtained from an in vivo study, which allowed derivation of equations (r=0.85). The equations were verified with six additional phenols, showing good correlations with the expected skin irritation scores. From the above findings, the equations can be considered useful for predicting the skin irritation potential of phenol compounds.

Mutagenicity of 4-nitroquinoline 1-oxide in the Muta Mouse

As part of a collaborative study, the Mammalian Mutagenesis Study Group (MMS), a sub-organization of the Environmental Mutagen Society of Japan (JEMS) conducted mutagenicity tests in MutaMouse. Using a positive selection method, we studied the organ-specificity and time dependence of mutation induction by 4-nitroquinoline 1-oxide (4NQO). A single dose of 4NQO was administered intraperitoneally (7.5 or 15 mg/kg) or orally (200 mg/kg) to groups of male mice. On days 7, 14 and 28 after treatment, we isolated the liver, kidney, lung, spleen, bone marrow, testis and stomach in the intraperitoneal administration experiment and the liver, lung, bone marrow, testis and stomach in the oral administration experiment. In addition, we performed the peripheral blood micronucleus test to evaluate clastogenicity. In the mice treated intraperitoneally at 7.5 mg/kg, we found increased mutant frequency (MF) only in the lung, where the MF did not vary with expression time. In the mice treated at 15 mg/kg, we found increased MF in the liver, bone marrow and lung. In orally treated mice, the MF was high in the lung and liver and very high in the bone marrow and stomach while the increase in the testis was negligible. As the expression time was prolonged, the MF tended to increase in the liver, decrease in the bone marrow, and remain stable in the lung, testis and stomach. The incidence of micronucleus induction in peripheral blood cells was significantly increased (p<0.01) in the 4NQO groups when compared with the vehicle control group by intraperitoneal treatment. Thus, these assay systems appeared to be of use in detecting not only genetic mutation but also chromosomal aberration.

[Analysis of acute toxicity (LD50-value) of organic chemicals to mammals by solubility parameter (delta). (1) Acute oral toxicity to rats].

Acute oral toxicity (LD50-value) of organic chemicals to rats was analyzed by using solubility parameter (delta c), a thermodynamic parameter, of the chemicals. Certain parabolic correlations were established between logarithm of LD50-value (mmol/kg body weight, rats) and delta c of all the collected chemicals (n = 144, R = 0.578), alcohols (n = 29, R = 0.587), ketones (n = 7, R = 0.962), aldehydes (n = 9, R = 0.621), ethers (n = 5, R = 0.890), acetates (n = 7, R = 0.670) and aromatics (n = 84, R = 0.736). Introducing molar volume (Vc) to the above equations could not improve the correlation. In the study, we assumed that as for acute toxicity, chemicals taken into the mammals through biological membrane first disturb the homeostasis, which causes certain biological reactions (i.e. death) and that amounts of the chemicals intaken are regulated by their solubility in the membrane. Based on the assumption, we drew a theoretical equation, which describes LD50 by a parabolic function of delta c. A regression analysis using the equation gave significant correlations as stated above, which incarnates the assumption. A solubility parameter of 2.30 x 10(4) (J/m3)1/2 was also determined for the biological membrane (absorption site) of rats. For comparison, log P was used to describe LD50 of all the chemicals, but no correlation was established (R = 0.164-0.443).

A new semi-automated chromosome analysis system for in vitro chromosomal aberration tests

We have evaluated a new semi-automated chromosome analysis system, employing the Magiscan human metaphase finder, for in vitro chromosomal aberration tests. The metaphases on a slide are recognized using the main system, a metaphase finder, and their stage coordinates are transferred to the satellite system, a computerized microscope with a motorized stage, by way of a diskette. In the satellite system, a researcher analyzes one metaphase after another at high power (100 x objective) without changing the objective. The effectiveness of the system, in comparison with the manual metaphase finding and analysis, was confirmed in in vitro chromosomal aberration tests using cultured Chinese hamster cells. Structural or numerical aberrations in the cells did not affect the metaphase findings. The system reduces the time for chromosome analysis by a factor of about 4. Moreover, the system provides perfect reproducibility for analyzing procedure. It is concluded that this semi-automated system is useful in in vitro chromosomal aberration tests.

A new fugacity model for aerial application of pesticides. Part I — The fate of a pesticide in the “spray zone” and the “adjacent zones”

Abstract A Level IV fugacity model was modified to build up a new one for aerial application of pesticides. The fugacity model developed by Mackay et al. can well describe the environmental fate of chemicals. However, the model is not applicable to non-gaseous chemicals, such as pesticides, when they are released directly into the atmosphere. This is because of a limiting assumption in the model that these chemicals must be instantaneously and evenly distributed in the atmosphere after the release, which is far different from actual observations. For the purpose of developing a suitable model for aerial application of pesticides to a forest, a new pesticide “droplet” compartment together with a “forest” one was introduced into the fugacity model; where the droplets with time, absorbed into forest, water and soil (the “spray zone”). The model was further expanded to describe the pesticide fate outside the “spray zone”. For the modelling, a typical land of square 10 km with atmosphere above is used as an environment. “Spray zone” with area of square 1 km is located in the center of the land and the surrounding land is divided into nine “adjacent zones” by a 500 m interval. Each “adjacent zone” has six compartments insides; air, water, soil, bottom sediment, suspended sediment and aquatic biota. When sprayed pesticide drifts to the “adjacent zones”, the “droplet” compartment, which has been generated in the “spray zone”, is added to the zones as a 7th compartment (the “adjacent zones”). A numerical solution of kinetics equations was made for the pesticide behavior in the “spray zone” and the “adjacent zones” in aerial application.

A fugacity model for aerial application of pesticides. Part II — The temperature-dependent changes of a pesticide fate

Abstract The temperature-dependent terms are introduced into modified fugacity models for aerial application of pesticides to predict temperature-dependent changes of the pesticide fate. In a simulation, temperature is varied from 18°C to 30°C and from 30°C to 18°C per 24 hours. The model describes the concentration of the released pesticide in air as a fuction of temperature. The calculated profiles are consistent with the data measured for Pesticide S in the field. The results suggest that the model is useful for predicting the temperature-dependent changes in behavior of the pesticide in aerial application.