Shoji Saito

Applicability of the i/o-characters to a quantitative description of bioconcentration of organic chemicals in fish

Abstract The bioconcentration factors (BCFs) of various types of organic chemicals in several fish species reported by Veith and Kosian were utilized to verify the applicability of ∑i and ∑o to describe their bioconcentration potentials quantitatively. A good linear correlation between logBCF and ∑i and ∑o was established over the 107 chemicals by a multiple regression: logBCF = −0.00458 ± (0.00089) · ∑i + 0.00991 ± (0.00036) · ∑o (n = 107, r 2 = 0.936, s = 0.735). The results suggest that ∑i and ∑o can be a good predictor of bioconcentration of organic chemicals in fish and broaden its applicability in this particular field.

[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).

Research to develop a predicting system of mammalian subacute toxicity, (3). Construction of a predictive toxicokinetics model.

A new predictive toxicokinetics model was developed to estimate subacute toxicity (target organs, severity, etc.) of non-congeneric industrial chemicals, where the chemical structures and physico-chemical properties are only available. Thus, a physiological pharmacokinetics model, which consists of blood, liver, kidney (these were experimentally found as major toxicological targets), muscle and fat compartments, was established to simulate the chemical concentrations in organs/tissues with pharmacokinetic parameters by means of Runge-Kutta-Gill algorithm. The pharmacokinetic parameters, i.e. absorption rate, absorption ratio, hepatic extraction ratio of metabolism and renal clearance were calculated by using separately established Quantitative Structure-Pharmacokinetics Relationship equations. The developed predictive model was then applied to simulations of 43 non-congeneric industrial chemicals. The chemical concentrations in organs/tissues after single oral administration were simulated, and their maximum concentrations (Cmaxs) and area under the concentration-time curves (AUCs) were calculated. Fast Inverse Laplace Transform was newly applied for the purpose of simulation of 28-day repeated dose toxicity. Simulated concentrations of 28 days repeated dose were, however, found to be the same as those of simple repetitions of a single administration per day because of the short half-lives of non-congeneric industrial chemicals. A comparison of subacute toxicity data with Cmaxs and AUCs in a single dose scenario suggested that the organs/tissues with relatively high concentrations of tested chemical substances were the most sensitive targets within a chemical. Chemical concentrations in liver, for instance, were correlated with the severity of hepatotoxicity among the chemicals. It was also suggested that to improve and widen the present approach, data of metabolite and reactivity of non-congeneric industrial chemicals to organs/tissues, receptors, etc. should be incorporated into the model.

Electron microscope autoradiographic examination of uptake behavior of lipophilic chemicals into fish gill

Juvenile carp (Cyprinus carpio) were exposed to fenvalerate and to an oligomer with molecular weights of 420 and 2,000-50,000 and log Po/w values of 6.4 and more than 14, respectively, and uptake behavior into gill tissues was observed by electron microscope autoradiography. It was qualitatively demonstrated that fenvalerate was absorbed into gill tissues and localized in membrane systems of each cell. On the other hand, no absorption was observed for the oligomer, even in the external membrane of pavement cells. These results suggest that absorption of the oligomer is limited by low diffusion into membranes due to its very high molecular weight, resulting in no bioconcentration in fish. The significance of log Po/w in uptake behavior is also verified from the distribution behavior of fenvalerate.

Effect of metabolism on bioconcentration of geometric isomers of d-phenothrin in fish

Abstract Yearling carp (Cyprinus carpio) were exposed to d-phenothrin (a 1:4 mixture of d-cis and d-trans isomers) in the absence and the presence of piperonyl butoxide under the flow-through test condition and the bioconcentration factors (BCFs) of the geometric isomers were separately evaluated. It was demonstrated that BCF values for the d-cis isomer were significantly higher by 1.1 to 2.2-fold than those for the d-trans isomer and the subsequent exposure in the presence of piperonyl butoxide resulted in elevated BCF values for the d-cis isomer, but no remarkable change in BCFs was observed for the d-trans isomer. The elevation observed here was presumably attributable to a reduced elimination caused by inhibited oxidative reactions characteristic to the d-cis isomer. The contribution of biotransformation to the elimination rate constant ( K 3 K 2 was estimated to be 2.3–11. Thus, the result was well explained by a distinct oxidative metabolism of the d-cis isomer and a significance of metabolism in bioconcentration phenomenon was exemplified.

The i/o-characters to evaluate n-octanol/water partition coefficient in bioconcentration of organic chemicals in fish

Abstract A good linear correlation (r2 = 0.944) between n-octanol/water partition coefficient (logP) and Fujitas ∑i and ∑o was established over the 128 organic compounds. The relationship was used to analyze those of bioconcentration factors (logBCF) in fish and logP. The results suggest that polar and nonpolar interaction patterns of a compound in n-octanol/water partitioning process can not match well with those in bioconcentration process enough to describe the phenomena.

The inorganic and organic characters for predicting bioconcentration on wide variety of chemicals in fish.

The applicability of Fujitas inorganic (i) and organic (o) characters as descriptors for predicting bioconcentration factor (BCF) in fish was investigated with a wide variety of organic chemicals. Among 612 BCF data recently released by National Institute of Technology and Evaluation (NITE), the values for the chemicals with a molecular weight of less than 600 and the 1-octanol/water partition coefficient (log P ) of less than six were extracted and analyzed. By applying theoretically derived model equation, a good relationship between these BCF and each Fujitas i: o was established. Statistical analyses and model validations revealed that the estimations of our approach were very excellent. More precise predictions were attained than those by using other published models, especially, for chemicals such as disperse dye having hetero atoms.

The i/o-characters related to the cohesive energy of organic chemicals

Abstract The cohesive energies of organic chemicals at boiling points and 25°C (ΔEbp and ΔE25) were attempted to correlate to the Fujitas i/o-characters and good linear relationships were established between individual cohesive energies Δ(ΔEbp) and Δ(ΔE25) and i+o of the functional group or unit in a molecule (r2 = 0.933 and 0.936) and between ΔEbp and ΔE25 and Σi+Σo of the molecule (r2 = 0.967 and 0.981). Thus, the parameter i+o acquired a thermodynamic basis, even though discrimination of i from o participating in the cohesive energy remained unsolved. The i/o-characters were proved to be additive in nature and thus, the molecule can be expressed as a summing-up of i and o, i.e. Σi+Σo. The results also showed that the i/o-characters can estimate quantitatively the cohesive energy of various organic chemicals.

The i/o-characters to describe bioconcentration of organic chemicals in fish

Abstract The bioconcentration factors (BCFs) of various kinds of organic chemicals in carp (Cyprinus carpio) were measured under the flow-through test conditions and a good linear correlation (r2=0.962) between the logBCFs and Fujitas ∑i and ∑o was established by a multiple regression. The result suggests that bioconcentration of organic chemicals in fish is controlled by quantum-chemical polar and nonpolar interactions between a compound and a fish tissue and water. Except for certain compounds with some uptake limitations, the parameters ∑i and ∑o can be a good predictor of bioconcentration of organic chemicals in fish.