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Correlations between pairs of simple physicochemical parameters of metal ions and acute toxicity in mice
The Science of the Total Environment, 68 (1988) 275-280
275
Elsevier Science Publishers B.V., Amsterdam -- Printed in The Netherlands
Short Communication CORRELATIONS BETWEEN PAIRS OF SIMPLE PHYSICOCHEMICAL PARAMETERS OF METAL IONS AND ACUTE TOXICITY IN MICE*
J.E. TURNER, M.W. ENGLAND and B.E. HINGERTY Health and Safety Research Division, Oak Ridge National Laboratory, P.O. Box X, Oak Ridge, TN 37831 (U.S.A.)
T.L. HAYDEN The University of Kentucky, Lexington, K Y 40506 (U.S.A.)
(Received June 25th, 1987; accepted August 20th, 1987)
ABSTRACT Our earlier study of correlations between single physical parameters characterizing divalent metal ions and their acute toxicity in mice is extended to linear combinations of pairs of parameters chosen from among the following five: ionic radius, sum of ionization potentials, atomic weight, Williams softness parameter, and electronegativity. Some improvements in the correlations are found by employing a two-parameter fit to a given set of toxicity data. Similar results are obtained when the grouping of metal ions is based on criteria suggested by Kaiser. INTRODUCTION I n a n earlier s t u d y we i n v e s t i g a t e d c o r r e l a t i o n s b e t w e e n single p h y s i c a l q u a n t i t i e s t h a t c h a r a c t e r i z e m e t a l ions a n d the a c u t e t o x i c i t y of the ions to mice ( T u r n e r et al., 1983). Table 1 lists the ions used a n d t h e i r observed toxicities, expressed in t e r m s of the 14-day LDs0 v a l u e in m m o l / k g of body w e i g h t from i.p. injection, as m e a s u r e d u n d e r u n i f o r m c o n d i t i o n s by Williams et al. (1982). F o r the 14 d i v a l e n t m e t a l ions used, the best c o r r e l a t i o n was f o u n d b e t w e e n the P e a r s o n - M a w b y (1967) c h e m i c a l softness p a r a m e t e r ap a n d LD~0. F o r one subset of 10 d i v a l e n t ions the c o r r e l a t i o n coefficient, r, b e t w e e n ap and LDs0 was as h i g h as 0.97. U n f o r t u n a t e l y , the P e a r s o n - M a w b y softness p a r a m e t e r c a n n o t be used to c o m p a r e ions h a v i n g different c h a r g e s (Ahrland, 1968). F o r this reason, T u r n e r et al. (1983) c o n c e n t r a t e d on d i v a l e n t ions. K a i s e r (1980) p r o p o s e d classifying m e t a l ions into t h r e e g r o u p s based on t h e i r o u t e r - e l e c t r o n c o n f i g u r a t i o n s . G r o u p 1 consists of ions w i t h c o m p l e t e l y filled p orbitals, G r o u p 2 of ions with p a r t l y or c o m p l e t e l y filled d orbitals, a n d * Research sponsored by the Office of Health and Environmental Research, U.S. Department of Energy, under contract DE-AC05-84OR21400with Martin Marietta Energy Systems, Inc.
0048-9697/88/$03.50
© 1988 Elsevier Publishers B.V.
276 TABLE 1 14-Day LDs0 values for metal ions in mice. From Williams et al. (1982) Ion
LD~0 (mmolkg 1)
Ag(I) Tl(I) Be(II) Mg(II) Mn(II) Co(II) Ni(II) Cu(II) Zn(II) Sr(II) Pd(II) Cd(II) Ba(II) Pt(II) Hg(II) Pb(II) Cr(III) Fe(III) Y(III) Rh(III) In(III) Gd(III) Au(III) Sn(IV)
0.14 0.14 0.23 4.1 0.73 0.48 0.29 0.063 0.18 4.7 0.47 O.O2O 0.21 0.16 0.024 0.46 0.80 1.2 O.52 1.4 0.040 1.8 0.20 0.38
G r o u p 3 of ions w i t h filled s orbitals. In t h e s t u d y r e p o r t e d by W i l l i a m s et al. (1982), LDs0 v a l u e s w e r e o b t a i n e d for 24 m e t a l ions. M o s t of t h e s e ions a r e e i t h e r in K a i s e r ' s G r o u p 1 or G r o u p 2. M o s t h a r d ions, c h a r a c t e r i z e d b y h i g h v a l u e s of ap, a r e i s o e l e c t r o n i c w i t h n o b l e gases a n d b e l o n g to G r o u p 1, while the soft ions, c h a r a c t e r i z e d by l o w e r v a l u e s of ap, b e l o n g to G r o u p 2. F o r m e t a l ions in e a c h of his groups, K a i s e r (1980) f o u n d t h a t r e p r o d u c t i v e i m p a i r m e n t to D a p h n i a m a g n a is d e s c r i b e d by the f o r m u l a pT
=
a + b log ( A N / A I P ) + c A E o
(1)
H e r e p T is the n e g a t i v e of t h e l o g a r i t h m of the ion c o n c e n t r a t i o n in mol l-1 t h a t g a v e a 16% i m p a i r m e n t in 3 weeks, A N is the a t o m i c n u m b e r of t h e metal, A I P is t h e d i f f e r e n c e (in eV) b e t w e e n the i o n i z a t i o n p o t e n t i a l of t h e ion a n d t h a t of t h e ion in its n e x t l o w e r o x i d a t i o n state, a n d AE0 is the m a g n i t u d e of the e l e c t r o c h e m i c a l p o t e n t i a l (in volts) b e t w e e n the ion a n d its first s t a b l e r e d u c e d state. T h e sets of coefficients a, b a n d c h a v e different n u m e r i c a l v a l u e s for the different g r o u p s of m e t a l ions. R e c e n t l y , K a i s e r (1985) applied a n e q u a t i o n of t h e f o r m a b o v e to d e s c r i b e the m o u s e d a t a of W i l l i a m s et al. (1982). C o r r e l a t i o n coefficients w e r e obtained between log LDs0 ( = - p T ) and linear
277 combinations of log (AN/AIP) and AE0. For the 15 metal ions in Group 2 having full or partially filled d-shells he found a correlation coefficient r = 0.87. For the four alkaline-earth ions in Group 1 he found r = 0.99 and, with the addition of Y(III), r = 0.75. The purpose of the present study is to extend the analysis of T u r n e r et al. (1983) by using linear combinations of two physical parameters in place of single parameters and by employing the groupings of Kaiser (1985). The correlation coefficients found by using linear combinations of two parameters must be at least as large as those found in the earlier analyses (Turner et al., 1983) when applied to the same group of metal ions. We have reported elsewhere on a different multivariate study (Turner et al., 1987) which lacked this advantage and did not lead to higher correlation coefficients. CHOICE OF PARAMETERS The most useful single parameters found from among the large number explored are, as seen from Table 4 in T u r n e r et al. (1983), the P e a r s o n - M a w b y softness p a r a m e t e r ap, the electrode potential EP (in volts), the Williams softness p a r a m e t e r aw, the sum of the ionization potentials IP (in eV), and the atomic weight A W. For the present work we make only incidental use of ap, since it should not be used to compare ions with different oxidation numbers. (In addition, numerical values of ap are not available for a number of metal ions.) Although we did not consider the ionic radius R (in A) earlier (Turner et al., 1983), we have found it to be useful when used in conjunction with other quantities. In addition, we shall use electronegativity x in place of EP, with which it is highly correlated. Thus the present paper concent rat es on correlations between our mouse toxicity data (Table 1) and linear combinations of pairs of the parameters R, IP, A W, aw and x. Numerical values of these five parameters are readily available in handbooks for most metal ions. The metal ions are grouped as before (Turner et al., 1983) and also as Kaiser (1985) has suggested. The data are fitted to equations of the form log LD~0 =
b0 + bl0)1 + b20)2
(2)
where 0)1 and 0)2 are two of the five basic physical parameters and b0, bl and b2 are constants obtained by least-squares fitting of the data. For the same groups of ions as used before, setting b2 = 0 in Eqn (2) reproduces the earlier results for each single par a m et er 0)1. Therefore, the correlation coefficient found for any pair of parameters, as represented by Eqn (2), cannot be smaller t h a n t hat found for either of the parameters used in a corresponding single-parameter fit. NUMERICAL RESULTS For easy reference, data from Table 4 of T u r n e r et al. (1983) are shown here in Table 2. For the group of eight divalent metal ions, Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II) and Pb(II), using Eqn (2) with 0)1 = ap and 0)2 = 0
278 TABLE 2 Correlation coefficients for LDs0 mouse data and single physicochemical parameters for sets of 8, 10, 11 and 14 divalent metal ions. From Table 4 of Turner et al. (1983) Parameter
Correlation coefficients, r Number of ions:
ap EP aw IP AW a
__
M n , C o , N i , Cu, Z n , - -
--
8a
l0 b
11¢
14d
0.94 0.59 0.61 0.73 0.33
0.97 0.84 0.69 0.83 0.43
0.81 0.69 0.69 0.60 0.44
0.60 0.57 0.52 0.55 0.38
Cd,--
--
H g , Pb.
b Mg, Mn, Co, Ni, Cu, Zn, S r , - - C d , - - - - Hg, Pb. c Mg, Mn, Co, Ni, Cu, Zn, Sr, - - Cd, Ba, - - Hg, Pb. dBe, Mg, Mn, Co, Ni, Cu, Zn, Sr, Pd, Cd, Ba, Pt, Hg, Pb. y i e l d s a c o r r e l a t i o n c o e f f i c i e n t r = 0.94 a s s h o w n i n T a b l e 2. I n a d d i t i o n , t h e s t a n d a r d d e v i a t i o n s = 0.23 a n d t h e l e v e l o f s i g n i f i c a n c e is 0.001. W h e n ch = ap a n d ~o2 is p u t e q u a l t o a n y o f t h e five q u a n t i t i e s R, IP, A W, a,, o r x, i n e a c h c a s e r -- 0.94, s = 0.24, a n d t h e l e v e l o f s i g n i f i c a n c e is 0.005. T h u s t h e r e w a s n o i m p r o v e m e n t o v e r u s i n g ap a l o n e . W i t h o u t ap, t h e h i g h e s t c o r r e l a t i o n coeff i c i e n t r = 0.90 (s = 0.32, l e v e l o f s i g n i f i c a n c e 0.025) w a s f o u n d b y u s i n g a c o m b i n a t i o n o f A W a n d aw. ( S e v e r a l o t h e r p a i r s y i e l d e d r ~ 0.85.) T a b l e 2 s h o w s t h a t , f o r A W o r aw a l o n e , t h e c o r r e l a t i o n c o e f f i c i e n t s a r e 0.33 (s = 0.62, l e v e l o f s i g n i f i c a n c e > 0.25) o r 0.61 (s = 0.52, l e v e l o f s i g n i f i c a n c e 0.25), r e s p e c tively. F o r t h e g r o u p o f 14 m e t a l i o n s f r o m T a b l e 2 o n l y a s l i g h t i m p r o v e m e n t o v e r r = 0.60 (s = 0.57, l e v e l o f s i g n i f i c a n c e 0.025) w a s f o u n d b y u s i n g ap a n d a n y o n e o f t h e five o t h e r p a r a m e t e r s , e.g. r = 0.63 (s = 0.58, l e v e l o f s i g n i f i c a n c e 0.1) w i t h ap a n d I P a n d w i t h ap a n d aw. H o w e v e r , c o n s i d e r a b l e i m p r o v e m e n t w a s o b t a i n e d f o r o t h e r p a r a m e t e r p a i r s n o t i n v o l v i n g ap. F o r e x a m p l e , t h e l a r g e s t v a l u e r = 0.76 (s = 0.49, l e v e l o f s i g n i f i c a n c e 0.01) w a s f o u n d f o r a l i n e a r c o m b i n a t i o n o f R a n d IP. A l s o , r = 0.71 (s = 0.53, l e v e l o f s i g n i f i c a n c e 0.025) f o r I P a n d aw. T h e s e r e s u l t s f o r t h e 14 m e t a l i o n s s h o w t h a t t h e b e s t fit o f a g i v e n set of toxicity data to a linear combination of two parameters need not involve the parameter that gives the highest single-parameter correlation. The equations describing these linear combinations of two parameters that give the h i g h e s t c o r r e l a t i o n c o e f f i c i e n t s f o r t h e 14 m e t a l i o n s a r e l o g LDs0 (n and
=
1.69 R - 0.153 I P + 4.66
-
14, r
=
0.76, s
=
0.49, l e v e l o f s i g n i f i c a n c e 0.01)
(3)
279 log LDs0 = 0.0796 I P (n =
0.231 aw + 2.58
(4)
14, r = 0.71, s = 0.53, level of significance 0.025).
We t u r n now to the metal ions listed in Table 1 and the five parameters R,
IP, A W, aw and x. Values for all five parameters are apparently not available for Gd(III) and Au(III), and so these ions were not considered further. As expected, based on Kaiser's work (1980, 1985), t reat i ng the remaining 22 metal ions as a single group did not give a high correlation coefficient for any linear combination of two of the five parameters. The largest value r = 0.54 (s -- 0.55, level of significance 0.05) was found for R and a~. Kaiser's groupings, on the other hand, led to significantly higher correlation coefficients for the p a r a m e t e r pairs. For the five " h a r d " ions [Be(II), Mg(II), Sr(II), Ba(II) and Y(III)] in Group 1, the highest correlation coefficients we found for pairs of parameters were in the range r = 0.87-0.89. However, because of the small number of metals, the level of significance was only 0.25. Fifteen of the ot her ions in Table 1 were treated as members of Kaiser's Group 2, Ag(I), Mn(II), Co(II),. Ni(II), Cu(II), Zn(II), Pd(II), Cd(II), Pt(II), Hg(II), Cr(III), Fe(III), Rh(III), In(III) and Sn(IV). The ionic radius R gives the best single-paramter fit from among the five quantities considered, with r = 0.60 (s = 0.50, level of significance 0.025). The highest correlation coefficient with two parameters, r = 0.72, was found by using the atomic weight and electronegativity: logLDs0 = (n =
-0.01lAW+
1.63x - 2.70
(5)
15, r = 0.72, s = 0.45, level of significance 0.025).
This compares with Kaiser's analysis of our LDs0 data (Kaiser, 1985) in which he obtained a value of r = 0.87 for Group 2 metal ions. SUMMARY Our earlier work (Turner et al., 1983) has been extended by (i) studying correlations with pairs of physical parameters and (ii) using the metal-ion groups of Kaiser (1980, 1985), As expected, for a given set of metal ions, equal or better correlations were obtained with the use of an additional parameter. It was also found t h a t the single par a met er with the largest correlation coefficient is not necessarily one of the pair t h a t gives the best correlation when two parameters are used. The usefulness of considering metal ions in the groups defined by Kaiser on physical grounds is confirmed, and the results of our analyses are compared with results obtained by him using different parameters. Two simple handbook parameters were not identified t h a t could give as good a correlation with our LDs0 data as his compound p a r a m e t e r AN/AIP combined with AE0. ACKNOWLEDGMENT The au th or s t h a n k Dr T.J. Mitchell for assistance with the data analysis.
280 REFERENCES Ahrland, S., 1968. Thermodynamics of complex formation between hard and soft acceptors and donors. Struct. Bonding, 5: 118-149. In particular, cf. p. 145. Kaiser, K.L.E., 1980. Correlation and prediction of metal toxicity to aquatic biota. Can. J. Fish. Aquat. Sci., 37: 211-218. Kaiser, K.L.E., 1985. Correlation of metal ion toxicities to mice. Sci. Total Environ., 46: 113-119. Pearson, R.G. and R.J. Mawby, 1967. The n a t u r e of metal-halogen bonds. In: V. G u t m a n n (Ed.), Halogen Chemistry, Vol. 3. Academic Press, London, pp. 55-84. Turner, J.E., E.H. Lee, K.B. Jacobson, N.T. Christie, M.W. Williams and J.D. Hoeschele, 1983. Investigation of correlations between chemical parameters of metal ions and acute toxicity in mice and Drosophila. Sci. Total Environ., 28: 343-354. Turner, J.E., M.W., Williams, B.E. Hingerty and T.L. Hayden, 1987. Multiparameter correlations between properties of metal ions and their acute toxicity in mice. In: K.L.E. Kaiser (Ed.), Proc. 2nd International Workshop on QSAR in Environmental Toxicology, Hamilton, Ontario, Canada, J u n e 9-13, 1986. D. Reidel, Dordrecht, pp. 375-383. Williams, M.W. (now M.W. England), J.D. Hoeschele, J.E. Turner, K.B. Jacobson and E.H. Lee, 1982. Chemical softness and acute metal toxicity in mice and Drosophila. Toxicol. Appl. Pharmacol., 63: 461-469.
275
Elsevier Science Publishers B.V., Amsterdam -- Printed in The Netherlands
Short Communication CORRELATIONS BETWEEN PAIRS OF SIMPLE PHYSICOCHEMICAL PARAMETERS OF METAL IONS AND ACUTE TOXICITY IN MICE*
J.E. TURNER, M.W. ENGLAND and B.E. HINGERTY Health and Safety Research Division, Oak Ridge National Laboratory, P.O. Box X, Oak Ridge, TN 37831 (U.S.A.)
T.L. HAYDEN The University of Kentucky, Lexington, K Y 40506 (U.S.A.)
(Received June 25th, 1987; accepted August 20th, 1987)
ABSTRACT Our earlier study of correlations between single physical parameters characterizing divalent metal ions and their acute toxicity in mice is extended to linear combinations of pairs of parameters chosen from among the following five: ionic radius, sum of ionization potentials, atomic weight, Williams softness parameter, and electronegativity. Some improvements in the correlations are found by employing a two-parameter fit to a given set of toxicity data. Similar results are obtained when the grouping of metal ions is based on criteria suggested by Kaiser. INTRODUCTION I n a n earlier s t u d y we i n v e s t i g a t e d c o r r e l a t i o n s b e t w e e n single p h y s i c a l q u a n t i t i e s t h a t c h a r a c t e r i z e m e t a l ions a n d the a c u t e t o x i c i t y of the ions to mice ( T u r n e r et al., 1983). Table 1 lists the ions used a n d t h e i r observed toxicities, expressed in t e r m s of the 14-day LDs0 v a l u e in m m o l / k g of body w e i g h t from i.p. injection, as m e a s u r e d u n d e r u n i f o r m c o n d i t i o n s by Williams et al. (1982). F o r the 14 d i v a l e n t m e t a l ions used, the best c o r r e l a t i o n was f o u n d b e t w e e n the P e a r s o n - M a w b y (1967) c h e m i c a l softness p a r a m e t e r ap a n d LD~0. F o r one subset of 10 d i v a l e n t ions the c o r r e l a t i o n coefficient, r, b e t w e e n ap and LDs0 was as h i g h as 0.97. U n f o r t u n a t e l y , the P e a r s o n - M a w b y softness p a r a m e t e r c a n n o t be used to c o m p a r e ions h a v i n g different c h a r g e s (Ahrland, 1968). F o r this reason, T u r n e r et al. (1983) c o n c e n t r a t e d on d i v a l e n t ions. K a i s e r (1980) p r o p o s e d classifying m e t a l ions into t h r e e g r o u p s based on t h e i r o u t e r - e l e c t r o n c o n f i g u r a t i o n s . G r o u p 1 consists of ions w i t h c o m p l e t e l y filled p orbitals, G r o u p 2 of ions with p a r t l y or c o m p l e t e l y filled d orbitals, a n d * Research sponsored by the Office of Health and Environmental Research, U.S. Department of Energy, under contract DE-AC05-84OR21400with Martin Marietta Energy Systems, Inc.
0048-9697/88/$03.50
© 1988 Elsevier Publishers B.V.
276 TABLE 1 14-Day LDs0 values for metal ions in mice. From Williams et al. (1982) Ion
LD~0 (mmolkg 1)
Ag(I) Tl(I) Be(II) Mg(II) Mn(II) Co(II) Ni(II) Cu(II) Zn(II) Sr(II) Pd(II) Cd(II) Ba(II) Pt(II) Hg(II) Pb(II) Cr(III) Fe(III) Y(III) Rh(III) In(III) Gd(III) Au(III) Sn(IV)
0.14 0.14 0.23 4.1 0.73 0.48 0.29 0.063 0.18 4.7 0.47 O.O2O 0.21 0.16 0.024 0.46 0.80 1.2 O.52 1.4 0.040 1.8 0.20 0.38
G r o u p 3 of ions w i t h filled s orbitals. In t h e s t u d y r e p o r t e d by W i l l i a m s et al. (1982), LDs0 v a l u e s w e r e o b t a i n e d for 24 m e t a l ions. M o s t of t h e s e ions a r e e i t h e r in K a i s e r ' s G r o u p 1 or G r o u p 2. M o s t h a r d ions, c h a r a c t e r i z e d b y h i g h v a l u e s of ap, a r e i s o e l e c t r o n i c w i t h n o b l e gases a n d b e l o n g to G r o u p 1, while the soft ions, c h a r a c t e r i z e d by l o w e r v a l u e s of ap, b e l o n g to G r o u p 2. F o r m e t a l ions in e a c h of his groups, K a i s e r (1980) f o u n d t h a t r e p r o d u c t i v e i m p a i r m e n t to D a p h n i a m a g n a is d e s c r i b e d by the f o r m u l a pT
=
a + b log ( A N / A I P ) + c A E o
(1)
H e r e p T is the n e g a t i v e of t h e l o g a r i t h m of the ion c o n c e n t r a t i o n in mol l-1 t h a t g a v e a 16% i m p a i r m e n t in 3 weeks, A N is the a t o m i c n u m b e r of t h e metal, A I P is t h e d i f f e r e n c e (in eV) b e t w e e n the i o n i z a t i o n p o t e n t i a l of t h e ion a n d t h a t of t h e ion in its n e x t l o w e r o x i d a t i o n state, a n d AE0 is the m a g n i t u d e of the e l e c t r o c h e m i c a l p o t e n t i a l (in volts) b e t w e e n the ion a n d its first s t a b l e r e d u c e d state. T h e sets of coefficients a, b a n d c h a v e different n u m e r i c a l v a l u e s for the different g r o u p s of m e t a l ions. R e c e n t l y , K a i s e r (1985) applied a n e q u a t i o n of t h e f o r m a b o v e to d e s c r i b e the m o u s e d a t a of W i l l i a m s et al. (1982). C o r r e l a t i o n coefficients w e r e obtained between log LDs0 ( = - p T ) and linear
277 combinations of log (AN/AIP) and AE0. For the 15 metal ions in Group 2 having full or partially filled d-shells he found a correlation coefficient r = 0.87. For the four alkaline-earth ions in Group 1 he found r = 0.99 and, with the addition of Y(III), r = 0.75. The purpose of the present study is to extend the analysis of T u r n e r et al. (1983) by using linear combinations of two physical parameters in place of single parameters and by employing the groupings of Kaiser (1985). The correlation coefficients found by using linear combinations of two parameters must be at least as large as those found in the earlier analyses (Turner et al., 1983) when applied to the same group of metal ions. We have reported elsewhere on a different multivariate study (Turner et al., 1987) which lacked this advantage and did not lead to higher correlation coefficients. CHOICE OF PARAMETERS The most useful single parameters found from among the large number explored are, as seen from Table 4 in T u r n e r et al. (1983), the P e a r s o n - M a w b y softness p a r a m e t e r ap, the electrode potential EP (in volts), the Williams softness p a r a m e t e r aw, the sum of the ionization potentials IP (in eV), and the atomic weight A W. For the present work we make only incidental use of ap, since it should not be used to compare ions with different oxidation numbers. (In addition, numerical values of ap are not available for a number of metal ions.) Although we did not consider the ionic radius R (in A) earlier (Turner et al., 1983), we have found it to be useful when used in conjunction with other quantities. In addition, we shall use electronegativity x in place of EP, with which it is highly correlated. Thus the present paper concent rat es on correlations between our mouse toxicity data (Table 1) and linear combinations of pairs of the parameters R, IP, A W, aw and x. Numerical values of these five parameters are readily available in handbooks for most metal ions. The metal ions are grouped as before (Turner et al., 1983) and also as Kaiser (1985) has suggested. The data are fitted to equations of the form log LD~0 =
b0 + bl0)1 + b20)2
(2)
where 0)1 and 0)2 are two of the five basic physical parameters and b0, bl and b2 are constants obtained by least-squares fitting of the data. For the same groups of ions as used before, setting b2 = 0 in Eqn (2) reproduces the earlier results for each single par a m et er 0)1. Therefore, the correlation coefficient found for any pair of parameters, as represented by Eqn (2), cannot be smaller t h a n t hat found for either of the parameters used in a corresponding single-parameter fit. NUMERICAL RESULTS For easy reference, data from Table 4 of T u r n e r et al. (1983) are shown here in Table 2. For the group of eight divalent metal ions, Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II) and Pb(II), using Eqn (2) with 0)1 = ap and 0)2 = 0
278 TABLE 2 Correlation coefficients for LDs0 mouse data and single physicochemical parameters for sets of 8, 10, 11 and 14 divalent metal ions. From Table 4 of Turner et al. (1983) Parameter
Correlation coefficients, r Number of ions:
ap EP aw IP AW a
__
M n , C o , N i , Cu, Z n , - -
--
8a
l0 b
11¢
14d
0.94 0.59 0.61 0.73 0.33
0.97 0.84 0.69 0.83 0.43
0.81 0.69 0.69 0.60 0.44
0.60 0.57 0.52 0.55 0.38
Cd,--
--
H g , Pb.
b Mg, Mn, Co, Ni, Cu, Zn, S r , - - C d , - - - - Hg, Pb. c Mg, Mn, Co, Ni, Cu, Zn, Sr, - - Cd, Ba, - - Hg, Pb. dBe, Mg, Mn, Co, Ni, Cu, Zn, Sr, Pd, Cd, Ba, Pt, Hg, Pb. y i e l d s a c o r r e l a t i o n c o e f f i c i e n t r = 0.94 a s s h o w n i n T a b l e 2. I n a d d i t i o n , t h e s t a n d a r d d e v i a t i o n s = 0.23 a n d t h e l e v e l o f s i g n i f i c a n c e is 0.001. W h e n ch = ap a n d ~o2 is p u t e q u a l t o a n y o f t h e five q u a n t i t i e s R, IP, A W, a,, o r x, i n e a c h c a s e r -- 0.94, s = 0.24, a n d t h e l e v e l o f s i g n i f i c a n c e is 0.005. T h u s t h e r e w a s n o i m p r o v e m e n t o v e r u s i n g ap a l o n e . W i t h o u t ap, t h e h i g h e s t c o r r e l a t i o n coeff i c i e n t r = 0.90 (s = 0.32, l e v e l o f s i g n i f i c a n c e 0.025) w a s f o u n d b y u s i n g a c o m b i n a t i o n o f A W a n d aw. ( S e v e r a l o t h e r p a i r s y i e l d e d r ~ 0.85.) T a b l e 2 s h o w s t h a t , f o r A W o r aw a l o n e , t h e c o r r e l a t i o n c o e f f i c i e n t s a r e 0.33 (s = 0.62, l e v e l o f s i g n i f i c a n c e > 0.25) o r 0.61 (s = 0.52, l e v e l o f s i g n i f i c a n c e 0.25), r e s p e c tively. F o r t h e g r o u p o f 14 m e t a l i o n s f r o m T a b l e 2 o n l y a s l i g h t i m p r o v e m e n t o v e r r = 0.60 (s = 0.57, l e v e l o f s i g n i f i c a n c e 0.025) w a s f o u n d b y u s i n g ap a n d a n y o n e o f t h e five o t h e r p a r a m e t e r s , e.g. r = 0.63 (s = 0.58, l e v e l o f s i g n i f i c a n c e 0.1) w i t h ap a n d I P a n d w i t h ap a n d aw. H o w e v e r , c o n s i d e r a b l e i m p r o v e m e n t w a s o b t a i n e d f o r o t h e r p a r a m e t e r p a i r s n o t i n v o l v i n g ap. F o r e x a m p l e , t h e l a r g e s t v a l u e r = 0.76 (s = 0.49, l e v e l o f s i g n i f i c a n c e 0.01) w a s f o u n d f o r a l i n e a r c o m b i n a t i o n o f R a n d IP. A l s o , r = 0.71 (s = 0.53, l e v e l o f s i g n i f i c a n c e 0.025) f o r I P a n d aw. T h e s e r e s u l t s f o r t h e 14 m e t a l i o n s s h o w t h a t t h e b e s t fit o f a g i v e n set of toxicity data to a linear combination of two parameters need not involve the parameter that gives the highest single-parameter correlation. The equations describing these linear combinations of two parameters that give the h i g h e s t c o r r e l a t i o n c o e f f i c i e n t s f o r t h e 14 m e t a l i o n s a r e l o g LDs0 (n and
=
1.69 R - 0.153 I P + 4.66
-
14, r
=
0.76, s
=
0.49, l e v e l o f s i g n i f i c a n c e 0.01)
(3)
279 log LDs0 = 0.0796 I P (n =
0.231 aw + 2.58
(4)
14, r = 0.71, s = 0.53, level of significance 0.025).
We t u r n now to the metal ions listed in Table 1 and the five parameters R,
IP, A W, aw and x. Values for all five parameters are apparently not available for Gd(III) and Au(III), and so these ions were not considered further. As expected, based on Kaiser's work (1980, 1985), t reat i ng the remaining 22 metal ions as a single group did not give a high correlation coefficient for any linear combination of two of the five parameters. The largest value r = 0.54 (s -- 0.55, level of significance 0.05) was found for R and a~. Kaiser's groupings, on the other hand, led to significantly higher correlation coefficients for the p a r a m e t e r pairs. For the five " h a r d " ions [Be(II), Mg(II), Sr(II), Ba(II) and Y(III)] in Group 1, the highest correlation coefficients we found for pairs of parameters were in the range r = 0.87-0.89. However, because of the small number of metals, the level of significance was only 0.25. Fifteen of the ot her ions in Table 1 were treated as members of Kaiser's Group 2, Ag(I), Mn(II), Co(II),. Ni(II), Cu(II), Zn(II), Pd(II), Cd(II), Pt(II), Hg(II), Cr(III), Fe(III), Rh(III), In(III) and Sn(IV). The ionic radius R gives the best single-paramter fit from among the five quantities considered, with r = 0.60 (s = 0.50, level of significance 0.025). The highest correlation coefficient with two parameters, r = 0.72, was found by using the atomic weight and electronegativity: logLDs0 = (n =
-0.01lAW+
1.63x - 2.70
(5)
15, r = 0.72, s = 0.45, level of significance 0.025).
This compares with Kaiser's analysis of our LDs0 data (Kaiser, 1985) in which he obtained a value of r = 0.87 for Group 2 metal ions. SUMMARY Our earlier work (Turner et al., 1983) has been extended by (i) studying correlations with pairs of physical parameters and (ii) using the metal-ion groups of Kaiser (1980, 1985), As expected, for a given set of metal ions, equal or better correlations were obtained with the use of an additional parameter. It was also found t h a t the single par a met er with the largest correlation coefficient is not necessarily one of the pair t h a t gives the best correlation when two parameters are used. The usefulness of considering metal ions in the groups defined by Kaiser on physical grounds is confirmed, and the results of our analyses are compared with results obtained by him using different parameters. Two simple handbook parameters were not identified t h a t could give as good a correlation with our LDs0 data as his compound p a r a m e t e r AN/AIP combined with AE0. ACKNOWLEDGMENT The au th or s t h a n k Dr T.J. Mitchell for assistance with the data analysis.
280 REFERENCES Ahrland, S., 1968. Thermodynamics of complex formation between hard and soft acceptors and donors. Struct. Bonding, 5: 118-149. In particular, cf. p. 145. Kaiser, K.L.E., 1980. Correlation and prediction of metal toxicity to aquatic biota. Can. J. Fish. Aquat. Sci., 37: 211-218. Kaiser, K.L.E., 1985. Correlation of metal ion toxicities to mice. Sci. Total Environ., 46: 113-119. Pearson, R.G. and R.J. Mawby, 1967. The n a t u r e of metal-halogen bonds. In: V. G u t m a n n (Ed.), Halogen Chemistry, Vol. 3. Academic Press, London, pp. 55-84. Turner, J.E., E.H. Lee, K.B. Jacobson, N.T. Christie, M.W. Williams and J.D. Hoeschele, 1983. Investigation of correlations between chemical parameters of metal ions and acute toxicity in mice and Drosophila. Sci. Total Environ., 28: 343-354. Turner, J.E., M.W., Williams, B.E. Hingerty and T.L. Hayden, 1987. Multiparameter correlations between properties of metal ions and their acute toxicity in mice. In: K.L.E. Kaiser (Ed.), Proc. 2nd International Workshop on QSAR in Environmental Toxicology, Hamilton, Ontario, Canada, J u n e 9-13, 1986. D. Reidel, Dordrecht, pp. 375-383. Williams, M.W. (now M.W. England), J.D. Hoeschele, J.E. Turner, K.B. Jacobson and E.H. Lee, 1982. Chemical softness and acute metal toxicity in mice and Drosophila. Toxicol. Appl. Pharmacol., 63: 461-469.