Document zo3Y837wz4Y4GkkDv43pG9pdR

Bull. Environ. Contam. Toxicol. (1986) 37:633-637 1986 Springer-Verlag New York Inc. J* Environmental Contamination and Ttaxicotogy Relationship Between Specific Molecular Connectivity Indices and Teratogenicity, Carcinogenicity, and Mutagenicity of Chlorinated Benzenes and a Biphenyl Makoto Murakami1* and Jun-ichi Fukami2 'Office for Life Science Promotion, The Institute of Physical and Chemical Research, 2-28-8, Honkomagome, Bunkyo-ku, Tokyo 113, Japan and laboratory of Insect Toxicology, The Institute of Physical and Chemical Research, Wako, Saitama 351-01, Japan The molecular connectivity value which is a measure of extent of molecular branching, increases with increasing molecular size. Therefore, to evaluate the structural information of molecular connectivity more pertinently, we introduced a concept of specific molecular connectiv ity which was the ratio of the molecular connectivity index to an information concerning the molecular size. Two specific molecular connectivity indices have been used in our studies: The zero-order specific molecular connectivity which is obtained by dividing the zero-or der molecular connectivity index (Sabljic 1983) with the number of non-hydrogen atoms in a molecule, and the second-order specific molecular connectivity which is obtained by dividing the second-order molecular connec tivity index (Kier and Hall 1977) with the number of mo lecular fragments consisting of three adjacent and con secutive non-hydrogen atoms. In this report we calcu late the zero-order and second-order specific molecular connectivity values of various chlorinated benzenes and a polychlorinated biphenyl, and examine the relation ships between these values and their mutagenic, carcino genic and teratogenic potentials and toxic effects as reported in the literature. MATERIALS AND METHODS The zero-order molecular connectivity index, X. , was calculated in the following fashion (Sabljic 1983) . Each non-hydrogen atom in a molecule is described by its delta value, , which is equal to the number of adja cent non-hydrogen atoms. The index is then calculated for each compound according to the expression: Correspondence and reprint requests 633 SL 03558^ n 0.5 j-1 where "n" is the number of non-hydrogen atoms in a mole cule. The zero-order specific molecular connectivity index is expressed as ,X/n- 2 The second-order molecular connectivity index, X./ refers to molecular fragments consisting of three adjacent and consecutive non-hvdrogen atoms (i,j and k)(Kier and Hall 1977) . The value of c^^ is computed as the reciprocal square root of the product of the delta values. (i$jk^ *5. These values are then summed by considering all molecular fragments in the molecule. The summarizing expression becomes where "s" is the number of molecular fragments consisting of three adjacent and consecutive non-hydrogen atoms in a molecule. The second-order specific molecular connec- tivity index is expressed as 2 %,/s. RESULTS AND DISCUSSION We previously calculated the zero-order specific molecu lar connectivity values of representative pesticides and related compounds and found that carbaryl had very low value as compared with other pesticides (Murakami and Fukami 1985). Since there is increasing concern over the reported teratogenic effects of this compound in mam mals (Fischbein 1976), we examined the relationships be tween the zero- and second-order specific molecular con nectivity indices and mutagenicity, carcinogenicity and teratogenicity of carbaryl and other carbamate pesticides as reported in the literature (Woo 1983). It was demon strated that carbaryl and benomyl had the lowest zp oand second-order specific molecular connectivity indices among the carbamates examined (Murakami and Fukami 1986). These two chemicals have positive evidence for terato genicity (Woo 1983). In the present study the validity of this specific molecular connectivity-teratogenicity relationship found in carbamate pesticides is examined for organochlorine compounds. 634 SL 035582 SL 035583 Table 1. Zero- and second-order specific molecular connectivity indices and the data on mutagenicity. carcinogenicity, teratogenicity and acute toxicity of chlorinated benzenes and a Li;\.cnyl Compound Mutagenicity Carcino Terato X/n 2X 2X/s genicity genicity LD50C Ames Other tests'3 Rat Mouse Rat Mouse (mg/kg) Hexachlorobenzene 3,4,S.l',4',s'- Hexachlorobiphenyl Pentachlorobenzene 1,2,4-Trichlorobenzene 1,2-Dichlorobenzene 1,4-Dichlorobenzene Monochlorobenzene 9.464 13.448 8.594 6.854 5.983 5.983 5.113 0.789 0.747 0.781 0.762 0.748 0.748 0.730 5.155 8.090 4.767 3.873 3.239 3.365 2.743 0.286 0.289 0.298 0.323 0.324 0.337 0.343 - n.t. -,+ ++ + ++ 32 0.5d + 940 n.t. n.t. 756 - 1516 - 1625 + n.t. n. t. 2190 a Mutagenic, carcinogenic and teratogenic potencies: +, active; -, inactive; n.t., not tested. A blank space indicates that these activities have not been reported. Mutagenic, carcinogenic and teratogenic potencies and values are quoted from a recent review article (Lai 1984). b The tests include mutagenicity assays using microbial and mammalian test systems and assays at the cellular and molecular levels except the Ames test (Lai 1984). The results obtained by using various methods are different in some cases. c Per oral acute LD=t> u- data for rats. d Per oral acute LDg0 data for guinea pigs. Lai DY (1984) Halogenated benzenes, naphthalenes, bi phenyls and terphenyls in the environment: Their carcinogenic, mutagenic and teratogenic potential and toxic effects. J Environ Sci Health 02:135-184 Maugh TH (1978) Chemicals: How many are there? Science 199:162 Murakami M, Fukami J (1985) Specific molecular connectiv ity analysis of pesticides and related compounds: A preliminary study. Bull Environ Contam Toxicol 34:775779 Murakami M, Fukami J (1986) Relationship between specific molecular connectivity indices and teratogenicity, car cinogenicity and mutagenicity of carbamate pesticides. Bull Environ Contam Toxicol (in press) Sabljic A (1983) Quantitative structure-toxicity rela tionship of chlorinated compounds: A molecular connec tivity investigation. Bull Environ Contam Toxicol 30: 80-83 Woo YT (1983) Carcinogenicity, mutagenicity and terato genicity of carbamates, thiocarbamates and related com pounds: An overview of structure-activity relationships and environmental concerns. J Environ Sci Health Cl: 97-133 Received April 3, 1986; accepted July 1, 1986. 637 SL 03558**