Critical Reviews in Environmental Control

ISSN: 1040-838X (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/best19

Structure activity relationships for the prediction

of biodegradability of environmental pollutants

S. V. Mani , D. W. Connell & R. D. Braddock

To cite this article: S. V. Mani , D. W. Connell & R. D. Braddock (1991) Structure activity
relationships for the prediction of biodegradability of environmental pollutants, Critical
Reviews in Environmental Control, 21:3-4, 217-236, DOI: 10.1080/10643389109388416

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 Critical Reviews in Environmental Control, 21(3,4): 217-236 (1991)

Structure Activity Relationships for the

Prediction of Biodegradability of
Environmental Pollutants
S. V. Mani, D. W. Connell, and R. D. Braddock
Division of Australian Environmental Studies, Griffith University, Nathan, Brisbane,
Queensland 4111, Australia
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ABSTRACT: This paper reviews the development of Structure Activity Relationships (SARs) and
Quantitative SARs (QSARs) for the prediction of biodegradability of environmental pollutants.
The utility of QSARs for biodegradation has been evaluated in the light of various physicochemical,
quantum, and molecular descriptors and biodegradation parameters. It has been suggested that
further development of successful QSARs for biodegradation should involve the establishment of
large and consistent biodegradation data bases and the identification descriptors that can relate well
to the mechanisms and rate limiting processes in the biodegradation sequence. Among the descriptors
studied, the quantum chemical-type descriptors appear to be most promising for the development
of QSARs for the prediction of biodegradability of environmental pollutants.

KEY WORDS: SARs, QSARs, biodegradability, pollutants, physicochemical properties, molec-

ular descriptors.

I. INTRODUCTION

In recent years, Structure Activity Relationships (SARs) have been widely

applied in the prediction of toxicity, bioaccumulation, and the distribution of
chemicals released into the environment. Based on suitable descriptors and pa-
rameters, SARs offer the potential to provide predictions of environmental activity
relatively easily. SARs can provide qualitative information as to how modification
of chemical structures results in changes in chemical or biological activity.1
However, information on the environmental pathways and distribution often re-
quires the development of Quantitative Structure Activity Relationships (QSARs)
between the fundamental quantitative characteristics of chemicals and their ac-
tivity. QSARs are mathematical relationships usually found between the biological
activity of chemicals and quantitative descriptors derived either experimentally
or based on the structure of the chemical. QSARs supplement and extend, rather
than replace, the experimental investigation of the environmental fate of a chemical.2

1040-838X/91/S.50
1991 by CRC Press, Inc.

217
 The development of QSARs commenced with the pioneering work of Meyer
and Overton about the turn of the century. This was extended by Hammett in
the 1930s, Taft in the 1950s, and Hansch in the 1960s. Originally, QSARs were
developed and used in the design of medicinal compounds and were used to
estimate and predict the effects of drugs. However, in the 1970s, the potential
of QSARs to assist in the task of assessing new chemicals and their pathways
and effects in environmental systems was recognized and a new area of research
was opened.
When a chemical is discharged into the environment, it is distributed into
the different phases such as water, air, soil, and biota. Eventually, an equilibrium
is reached and this depends upon the properties of the phases and also the prop-
erties of the chemical.3 Biodegradation is one of the most important transformation
processes affecting the pathways and lodgement of chemicals in the environment.
This process determines the persistence of a chemical in a particular phase after
discharge occurs. Biodegradation refers to degradation of environmental pollu-
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tants by all biota, but is frequently used to imply degradation by microorganisms

only: such organisms account for the largest proportion of biological degradation
in the environment.4 A scheme illustrating the various processes involved in the
biodgradation of organic environmental pollutants is given in Figure 1.
There are a range of processes in the environment involved with overall
biodgradation of a chemical, any one of which may be rate determining. The
development of QSARs for biodgradation will be facilitated if one of the pro-
cesses is rate determining or dominant. Because of the complexities involved,
most of the relationships which have been developed for biodgradation are
qualitative or semi-quantitative in nature.5
Water provides a more environmentally effective medium than air or soil for
most chemicals. Aquatic biota can be subject to more uniform and dispersed
concentrations of chemicals. Solubility in air is generally very small and chemicals
precipitate out more readily than in water. Movement of chemicals in soils gen-
erally depends on moisture content, and the distribution is generally very local.
Water-based biota are generally more sensitive or reactive to the presence of
chemicals in the ambient environment than terrestrial organisms. Terrestrial or-
ganisms, especially soil-based biota, are particularly adept at degrading chemicals.
The objectives of this study are to review the existing QSARs and to evaluate
the utility of various descriptors and degradation parameters for predicting the
environmental activity of chemicals.
Most studies of QSARs in the literature are performed on small subsets of
chemicals for which appropriate values are known. Frequently, these data sets
are collected from a variety of experiments or from suitable computer models of
chemicals. Frequently, it is difficult to get consistent sets of data even for the
one chemical. As a result, most of the QSARs are statistically based.

218
 DISTRIBUTION AND TRANSPORT
PROCESSES IN THE ENVIRONMENT

I
UPTAKE PROCESSES BY ORGANISM

INTERNAL DISTRIBUTION PROCESSES

AND POSSIBLE BIOACCUMULATION

I
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POSSIBLE INDUCTION OF
ENZYMIC PROCESSES

i
BIODEGRADATION BY ORGANISM'S
METABOLIC PROCESSES

J
ELIMINATION FROM ORGANISM

FIGURE 1. Processes involved in the bio-

degradation of organic environmental pollut-
ants.

II. DESCRIPTORS USED IN SARs

A. Introduction

The success of a particular SAR in predicting toxicity and degradation depends

on the rate limiting process in a particular biodgradation reaction sequence, and
on how well the selected descriptor encapsulates the operation of this process.
Frequently, for a particular chemical, a specific descriptor which correlates well

219
 with a particular chemical in one set of experiments may produce a poor correlation
with a second set of experiments conducted under different conditions.
The differences may arise from a change in the rate limiting process in the
biodgradation sequence, where the original descriptor may no longer be appro-
priate. Descriptors can be based on molecular, physicochemical, thermodynamic,
or quantum chemical properties of the chemicals or compounds under consid-
eration. Sets of homologous compounds tend to give good relationships with all
descriptors whereas more diverse groups of chemicals give better results with
specific descriptors. A schematic illustration of the interrelationships between the
various properties and descriptors of a compound is presented in Figure 2. The
horizontal axis represents increasing complexity: at the left hand end are molecular
descriptors, while system-based descriptors are located to the right. As a general

INCREASING COMPLEXITY
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THERMODYNAMIC
PROPERTIES
(Descriptor examples:
field constant, resonance constant)

PHYSICAL PHYSICOCHEMICAL BIOLOGICAL

CHARACTERISTICS PROPERTIES PROPERTIES
OF MOLECULES ^ . (Descriptor examples: ^ (Descriptor examples:
(Descriptor examples: K,,,, molar refraction) bioaccumulation factor,
Randic Index, molecular LQo, biodgradation
weight) rate constant)

QUANTUM CHEMICAL
PROPERTIES
(Descriptor examples:
atomic charge, electronic charge)

FIGURE 2. Diagrammatic illustration of the interrelationships between the

various properties and descriptors of a compound.

220
 rule, descriptors most closely related to the rate limiting process being modeled
yield the best results. For example the Kw (octanol-to-water partition coefficient)
values yield the best descriptors for concentration processes. This suggests that
the best descriptors for the biodgradation process itself will be found in the
thermodynamic, physicochemical, and quantum chemical properties. Examples
of characteristics potentially useful with various stages of the biodgradation
process are shown in Table 1. Only a few typical descriptors are given, but these
are representative of the measures used to describe the process in question. A
large number of descriptors have been reported in the literature6 for the devel-
opment of SARs. Some of the characteristics of descriptors which are potentially
useful for describing biodgradation are presented in Table 2. These descriptors
can be used in less complex environmental situations involving chemical release.
The more complex situation to the right in Figure 2 involves biological properties,
particularly of the participating organism, and requires descriptors with an av-
eraging property over ensembles. While some of these characteristic descriptors
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have been developed, their use is less wide spread and their predictive capacity
is not high.

B. Molecular Descriptors

In recent years, molecular descriptors, such as the molecular surface area and
volume, have been used in the prediction of biological properties.7 For example,
Solvent Accessible Molecular Surface Area (SASA) and Solvent Accessible Mo-
lecular Volume (SAV) have been found to be particularly useful in predicting
the bioconcentration of lipophilic compounds in aquatic organisms.8 This is a
result of the bioconcentration phenomena being partially related to the area of
interface between the hydrophobic molecules and water.
Among the wide range of topological indices available, the molecular con-
nectivity indices have been most widely used9 in the prediction of biodegrada-
bility. Molecular connectivity was initially proposed by Randic10 in an attempt
to devise a quantitative measure of branching molecules, and was further devel-
oped by Kier and Hall.11 Molecular connectivities have been successfully used
by En'slein et al.,12 Boethling,9 and Niemi et al.13 in the development of rela-
tionships with biodegradability. However, these descriptors cannot explain whether
the effect of molecular structure on biological activity is steric dependence of a
compound on fitting into the active site of an enzyme, or electronic dependence
on substituent type.

C. Physicochemical Properties

Early studies on SARs have involved the correlation of biological activity

with physicochemical properties such as the octanol-water partition coefficient
K,,,,, usually expressed as (log K ^ ) , aqueous solubility, density, boiling point,

221
 TABLE 1
Examples of Properties and Descriptors Potentially Useful with Various Stages of
the Biodegradation Process

Quantum
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Useful molecular Physicochemlcal Thermodynamlc chemical

Process descriptors properties descriptors descriptors

Uptake by organism Molecular weight Water solubility Not appropriate Not

appropriate
Internal distribution Molecular surface LogK, Not appropriate Not
and bioaccumulation area appropriate
Biodegradation by Randic index Molar refraction Field constant Atomic
metabolic processes charge
 TABLE 2
Some Characteristics of Typical Descriptors

Class Name of descriptor Characteristics

Molecular Randic index A topological index which can be calculated

from the molecular structure of a molecule
and provides a quantitative measure of the
shape of the molecule
Physicochemical LoglC A quantitative experimental measurement of
the octanol-to-water partition coefficient
Thermodynamic Field constant (F) A numerical constant which quantifies the ef-
fect of an aromatic substituent and, in particu-
lar, describes a substituent's inductive or
electronegative nature
Quantum Atomic charge An electronic parameter which can be calcu-
chemical lated from the atomic structure of a compound
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and provides a quantitative measure of the ef-

fect of electronic factors

and molecular weight. Among these descriptors, log Kw has been widely used
in biodegradability studies. The processes by which the chemical becomes dis-
tributed and available in water are dependent on measures of its solubility. Where
this process becomes rate limiting, then such descriptors are good indicators for
the development of QSARs. The Kow value has been found to predict bioaccu-
mulation and hence it relates to degradation parameters particularly among groups
of structurally similar compounds. Studies involving log Kw as a descriptor have
been reported by Yonezawa and Urushigwa,14 Urushigwa and Yonezawa,15 Wolfe
et al.16 and Banerjee et al.17 in the prediction of biodegradability of various organic
compounds. Urushigwa and Yonezawa13 have found that the reverse-phase HPLC
retention time correlates well with log K ^ and hence is a suitable descriptor to
correlate with the rate of biodgradation. Log Kow alone is not a suitable char-
acteristic to describe the biodegradability of structurally dissimilar compounds
and compounds having dissimilar substituent groups. Thus, log K^, is often used
in conjunction with other parameters to account for the various substituent effects.18

D. Thermodynamic Descriptors

Thermodynamic parameters have been employed in SAR analysis in order

to quantify the particular effect due to different substituents in aromatic com-
pounds. Such descriptors relate to the underlying attack on the chemical compound
by enzyme-induced or other chemical reactions with an organism.
For example, Field Constant (F) and Resonance Constant (R) have been the
commonly employed thermodynamic parameters in SARs. The Field Constant,
F, is a numerical value which describes a substituent's ability to increase resonance
in an aromatic ring system.

223
 The numerical values of F and R were calculated by Hansch et al.19 using
the following Equations 1 and 2.

F = (1.369)(o-J - (O.373)(CTP) - 0.009 (1)

R = CTP - (0.921)(F) (2)

In Equations 1 and 2, the terms crm andCTPare the electronic constants calculated
through the use of linear free energy relationships (LFER) originally developed
by Hammett.20

E. Quantum Chemical Descriptors

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The application of quantum chemical descriptors in the development of S ARs

has only developed in recent times. The ready availability of computing techniques
has enabled the easy calculation of some of these parameters such as atomic
charge, electronic energy, ionization potential and dipole moment. Computational
packages such as COSMIC and MOPAC are able to calculate estimates of such
parameters.
Dearden and Nicholson21 were able to correlate the atomic charge difference
across a particular bond in a series of compounds to their biodegradability. The
data set contained mixed aromatic and aliphatic amines, phenols, mixed aromatic
and aliphatic aldehydes, carboxylic acids, and halogenated hydrocarbons.
Dearden and Nicholson22 suggested that for hydrocarbons the electronic en-
ergy (E) correlated well with biochemical oxygen demand (BOD) and thus is a
suitable parameter for this group.
Another descriptor suggested by Dearden and Nicholson22 was superdelo-
calizability. This is a measure of the reactivity of an atomic center which cor-
responds to the carbon atom to which a functional group is attached. This does
not necessarily mean that the attack on the molecule occurs at this atom, but it
indicates that the functional group controls the attack. Dearden and Nicholson22
further suggested that the reactivity of an atomic center relates only to the initial
chemical degradation step and that this step is rate controlling. The particular
value of this characteristic is that a single descriptor may possibly characterize
the biodegradability of a number of structurally diverse compounds without the
need for additional parameters representing substituent and other effects. How-
ever, there is the possibility of incorporating other descriptors such as ionization
potential and dipole moment in S ARs for biodegradability. These could extend
and improve the applicability and accuracy of SARs which may be developed in
the future. Only a few descriptors have the potential to account for the biode-
gradability of a wide variety of structurally diverse compounds. Furthermore,
since biodgradation involves a complex chain of reactions which may be specific
to an organism or species, most of the descriptors cannot quantify degradation
for a range of organisms and types of compounds.

224
 F. Group Contribution Descriptors

The group contribution approach is frequently used for the estimation of pure
component thermodynamic properties like heat capacities and critical constants
of various organic compounds. Desai et al.23 have recently reported the application
of a "Group Contribution method" for the prediction of biodgradation rate
constants of various compounds. The central idea of this method is to divide the
molecule of a compound into functional groups or their fragments, each having
a unique and known contribution to the property of interest. Addition of the values
for each fragment or group yields a measure of the overall biodgradation capacity
of the complete molecule. This approach appears to be promising for developing
QSARs for biodgradation since the calculation of biodgradation values for a
relatively small number of functional groups or their fragments enables application
to the large number of chemicals that contain these groups.
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The biodgradation rate constant K of a compound is given by

ln(K) = f(a,,a 2 ,. . .,a n ) (3)

where a ; are the contribution toward the property of interest from various func-
tional groups or fragments (see Table III in Reference 23). Expanding the above
function into a Taylor's series and neglecting the terms from second order, the
first order approximation of biodgradation rate constant K is given as

n
ln(K) = 2 a,N, (4)

where Nj is the number of groups of type i in the compound. A disadvantage of

this model is that, being a first order approximation, the model will break down
if interaction between groups becomes important: in these circumstances, the
higher order terms in the expansion may need to be considered. The details of
the groups studied by Desai et al.23 and their contribution of property values 04
are presented in Table 3.
Hansch and Leo24 developed a group parameter with numerical values that
can be calculated from the following Equation 5,

it = log(PJ - log(Py) (5)

where Px is the octanol-water partition coefficient for the substituted compound

and Py is the octanol-water partition coefficient for the unsubstituted compound.
Although these parameters have not been employed for the quantitative prediction
of biodegradability, they have potential value since they may provide an insight
into the effects of substituents on the rate of biodgradation.

225
 TABLE 3
Groups and Their Contribution
Values

Group i

Methyl (CH3) -1.3667

Mthylne (CH2) -0.0438
Hydroxy (OH) -1.7088
Acid (COOH) -1.3133
Ketone (CO) -0.5073
Amine (NH2) -1.4654
Aromatic CH (ACH) -1.5016
Aromatic carbon (AC) 1.0659

III. BIODEGRADATION PARAMETERS USED IN SARs

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A. Introduction

The development of a satisfactory SAR for a wide range of chemicals requires

a large and self-consistent data base on the biodgradation characteristics of
chemicals. Most of the studies reported on SARs have expressed the biodgra-
dation in terms of BOD, chemical oxygen demand (COD), and the first and
second order rate constants. A major problem in the development of a large
biodgradation data base is that different sets of data have been obtained using
different experimental procedures under a wide range of conditions.
Often different experimental methods may result in widely varying results
for the same compound. Hence, it is often difficult to collate the data into a
consistent data base. Another problem with the available data is that some ex-
perimental procedures have not allowed the acclimation of organisms (enzyme
induction, mutation, etc.). Usually, this is observed as a time lag between the
induction of the chemical and the beginning of degradation.

B. Biochemical Oxygen Demand

BOD is used as a parameter for estimating water quality but is also a measure
of the oxygen consumption during biodgradation under standard conditions. BOD
can be measured in the laboratory with reasonable reproducibility and a few
studies have been reported on the application of BOD in the development of
SARs. 12 ' 21 The basis of the technique involves dissolving the substance under
investigation in water, inoculating with bacterial culture, and incubating for a
standard time period. Measurement of the dissolved oxygen at the start and
completion of the experiment yields a measure of the amount of oxygen consumed
and hence a measure of the biodgradation which has occurred.
This method has the advantage that it is simple and can be carried out easily
under standard conditions allowing comparison from different laboratories. The

226
 culture used as an inoculum can differ between laboratories leading to variations
in results obtained.
In spite of this, absolute evaluation of biodegradability according to BOD is
difficult since the ratio of oxidation and synthesis of new biomass could vary
among different organic substances due to the effects of inhibition.

C. Chemical Oxygen Demand

The experimental measurement of degradability can be based on the decrease

of total organic carbon in the biological medium. Konecky et al.25 were the first
to evaluate degradability in terms of COD decrease and this was later pursued
by Janicke26 and Pitter.27 This method basically involves the use of strong oxi-
dizing agents, such as potassium dichromate or potassium permanganate, which
oxidize all the organic compounds present to carbon dioxide. By estimation of
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the oxidizing agent remaining after treatment with the reducing agent, an eval-
uation of the total oxidizable organic matter present at any given time can be
obtained in terms of the oxygen used to convert it to carbon dioxide. Methods
for the determination of total organic carbon by measurement of COD have been
described by Meissner28 and Pitter.29
This evaluation of biodegradability in terms of the decrease of organic carbon
has an advantage in that it gives a good representation of the amount of total
removable organic substrate irrespective of its chemical form. Furthermore, the
degree and rate of degradation can be expressed quantitatively with satisfactory
reliability.

D. Degradation Rate Constants

Development of QSARs for biodgradation often utilizes the first or second

order rate constants as biodgradation characteristics. Biodegradation data have
been reported for various classes of compounds in terms of biodgradation rate
constants by Wolfe et al., 16 and Paris et al.30> 31
The kinetics of biodgradation are represented generally by Monod's equation
for microbial growth,32 e.g.,

V
V = *(S) (6)
w
K* + (S)
where V and V* represent the actual and maximum growth rates, K* is the
substrate concentration required to reach half the maximum rate, and S is substrate
concentration. Equation 6 is analogous to the Michaelis-Menten equation for
enzymatic degradation processes.

227
 Following Equation 6, the rate of degradation of a compound is given by

d(S) V*(S)(B)
dt Y(K* + (S))
(7)

where S and B represent the substrate and biomass concentration, respectively,

and Y is a yield factor.
If the substrate concentration is much greater than K*, then Equation 7 reduces
to

dt Y
(8)
= k,(B)
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where k, = V*/Y.
In Equation 8, the rate of substrate depletion is independent of substrate
concentration and is dependent only on microbial concentration. Hence, the rate
is first order and k, is a first order rate constant.
On the other hand, if the substrate concentration is much lower than K*, then
Equation 7 reduces to

0*3)
(9)

= k2(B)(S)

where k2 = V*/YK*.
Equation 9 is second order since the rate of substrate depletion is dependent
on both the substrate and microbial concentrations and k2 is a second order rate
constant. In the environmental degradation of pollutant compounds, low substrate
concentrations commonly occur and hence the second order rate constant may
be a more appropriate measure of the biodgradation rate.
The second order rate equation has been applied successfully to the biodg-
radation of various classes of compounds using both pure and mixed cul-
tures.9- 16> 33> M However, the validity of Equation 8 can be in question since it is
assumed that S is much lower than K*. Often the concentration of pollutants in
natural waters is at very low levels thus raising a question as to the validity of
this assumption. Hence, more data are needed for K* so that the applicability of
the second order model can be verified for various environmental situations.
Furthermore, Rubin et al.35 suggested that, in natural environments, the organisms
responsible for the degradation of organic chemicals at low concentrations could
be different from those that carry out degradation at higher substrate concentra-
tions. This implies that the rate constants determined in a particular study at low

228
 substrate concentrations may not reflect degradation kinetics at higher
concentrations.

IV. OBSERVED STRUCTURE BIODEGRADABILITY RELATIONSHIPS

A. Introduction

The environmental biodgradation of organic compounds involves a complex

interplay of organism type, degradation environment, chemical structures, and
biochemical reactions. Hence, the development of quantitative relationships pre-
sents a number of difficulties and, as a result, few studies have been reported.
Some of the earlier studies resulted in the development of some qualitative re-
lationships between chemical structure and biodegradability. These qualitative
relationships have facilitated the synthesis of environmentally compatible com-
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pounds and have provided a general basis for the prediction of microbial break-
down of organic compounds in the environment.
Most of the structure activity relationships reported are dependent upon the
quality of the data set and the nature of the descriptors used. Statistical techniques
commonly used in the correlation include discriminant analysis, cluster analysis,
and linear and multilinear regression. Studies involving qualitative SARs have
adopted discriminant and cluster analysis, while linear and multilinear regression
have also been used for quantitative relationships.

B. Qualitative Observations on Structural Characteristics

Influencing Biodegradation

Compounds containing highly branched alkyl chains degrade slowly as ob-

served from the degradation of surfactants by Swisher.36 On the other hand,
functional groups such as hydroxyl and carboxylate groups on benzene rings
increase biodegradability, while halogen, nitro, and sulfonate groups decrease
biodgradation.37 Ortho-substituted aromatic compounds are slightly more bio-
degradable than para-substituted compounds, and the meta-substituted compounds
have the least biodegradable substitution pattern. The information also suggests
that compounds containing either pattern are resistant to biodgradation. Other
qualitative relationships imply that, as a general rule, water-soluble chemicals
are usually more biogradable than insoluble chemicals.38 These qualitative rela-
tionships have facilitated the synthesis and development of compounds which
may be discharged to the environment with some degree of safety. An example
of this is the replacement of alkyl benzene sulfonate surfactants with linear alkyl
sulfonate surfactants in detergents. Although these qualitative relationships illus-
trate the utility of chemical structure and biodegradability relationships, their
application is limited by their qualitative and empirical nature.

229
 C. Quantitative Relationships Based on Various Descriptors and
Physicochemical Properties

The development of quantitative relationships between chemical character-

istics and biodegradability have mainly involved the development of SARs from
empirical biodgradation data. For example Yonezawa and Urushigwa14 devel-
oped correlations between the rate of biodgradation of aliphatic alcohols in an
activated sludge and their calculated octanol-water partition coefficients. The
biodgradation rate constants were obtained by a modified flask biodgradation
procedure.39 The biodgradation rate constants decreased with increasing partition
coefficients and then started to increase for alcohols with partition coefficients
> 100. These results were interpreted as indicating that uptake of these compounds
by diffusion was the process determining their degradation rate. However, the
data analysis does not provide any insight into the effects of substituents on the
degradation of alcohols. In a similar study, Urushigwa and Yonezawa15 correlated
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the rate constants for n-alkyl phthalate esters with their reverse-phase HPLC
retention times (Figure 3). The HPLC retention times correlated well with partition
between water and organic phases such as octanol. Interestingly, the biodgra-
dation rate decreased for the most hydrophobic compound.
Wolfe at al.16 have correlated the rate of biodgradation with the second order
alkaline chemical hydrolysis rate and the octanol-water partition coefficients of
various compounds. The initial step in the degradation was hydrolysis of an ester
linkage in all of the compounds and their rates correlated well with their chemical
properties.
Paris et al.30 studied eight para-substituted phenols and developed linear
correlations between the rate of biodgradation and the Van der Waals radii of
the substituents. The linear regression equation obtained was

Log k = - I . 3 6 7 - 9.3, n = 8, r = 0.978 (10)

where k is the rate constant of oxidation and y is the Van der Waals radius of
the substituent.
Mudder18 used multiple-linear regression to correlate degradation rate data.
The basic data were generated by Pitter29 using a data set containing compounds
with diverse chemical structures, a range of physicochemical properties, as well
as structural and electronic parameters. However, the use of a large number of
variables with a limited data set can result in chance correlations. Furthermore,
the use of a large number of variables may result in regression coefficients that
depend on few data points and hence are not accurate or reliable.
Some investigations have concentrated on the relationship of biodegradability
to lipophilicity. For example, Paris et al.40 correlated the microbial transformation
rate constants of carboxylic acid esters (with a fixed aromatic moiety and in-
creasing length of alkyl compounds) and ethyl esters of chlorine substituted
carboxylic acids with the octanol-water partition coefficients. The regression
coefficients for the linear relationship for the carboxylic acid esters were found

230
 -3.0 -

s ~
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-4.0
0.5 1.0

LOG RT (min)

FIGURE 3. Correlation of first order biodgradation rate constants (K^) with reverse-phase
HPLC retention times (Ft,) for di-n-alkyl phthalates.15

to be higher than the ethyl esters of chlorine substituted carboxylic acids. This
study indicated that not only the lipophilicity of the compound but also the
proximity to the reaction site is also important to the degradation process.
Similarly, Banerjee et al.17 found a relationship between lipophilicity and the
rate of degradation of chlorophenols and related compounds. The rate increased
with decreasing lipophilicity and then leveled off. A model for the semi-quan-
titative evaluation of these rates was proposed on the assumption that penetration
of the bacterial cell membrane is the rate determining step and the enzymes
capable of degrading the compounds are readily available internally. However,
the limitation of the model is that it assumes a constant degradation mechanism
for all compounds.

231
 Pitter41 observed that, for a series of anilines and phenols, the rate of bio-
degradation is dependent upon electronic factors. For example, for O-substituted
phenols, he obtained

log v = - 0 . 4 3 a + 1.7; n = 5, r = 0.98 (11)

where v is the specific rate of biodgradation and cr is the Hammett substituent

constant.
Boethling9 applied molecular connnectivities to the development of quanti-
tative correlations with the rate constants of biodgradation for 2,4-D alkyl esters,
N-3-chlorophenyl carbamates, dialkyl ethers, and dialkyl phthalate esters. Models
involving two variables substantially improved the correlations for biodgradation
of aliphatic alcohols and acids compared to single variable models, and the effect
of alkyl chain branching could be quantitatively described by connectivity indices.
However, Boethling9 also found good correlations of the same biodgradation
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data with log Kw and molecular weight. This suggests that the relationships thus
established are only applicable to the compound groups for which they were
developed. For example, the phthalate esters form a homologous series and it
should be possible to relate their degradation constants with other descriptors of
size such as molecular volume or solvent accessible surface area. Topological
descriptors seem promising for developing quantitative relationships but they
cannot explain the effect of electronic factors.
Dearden and Nicholson21 developed quantitative correlations between the
modulus of atomic charge difference across a particular bond in a molecule and
the 5-day BOD values for a wide range of different classes of compounds. In
these relationships, since the regression coefficient is close to 1 x 103 in each
case and the constant terms (intercept) are close to zero, the data can be combined
into a single equation representing all the compounds considered as given below.

BOD = (1.015 x 103) A/5/x_y + 1.193; n = 79, r = 0.93, s = 3.459 (12)

From Equation 12, it is evident that the calculation of a single parameter for a
compound enables a good prediction of its BOD value. Even though the atomic
charge difference appears to be a controlling factor for biodgradation, an ex-
planation of this effect is not available yet. Furthermore, the use of quantitative
BOD values in developing the correlations may not be fully satisfactory due to
the unreliability of BOD data produced by different experimental situations.
However, the A//x.y parameter appears to be a promising descriptor for the
quantitative prediction of biogradability.
In a similar study, Dearden and Nicholson22 included additional classes of
compounds to correlate the atomic charge difference with BOD. It is interesting
to note that similar correlations could not be obtained for hydrocarbons since
they do not contain any functional groups.
In a subsequent study by Dearden and Nicholson,42 they attempted to eliminate
the modulus used in the earlier study and hypothesized that the square of the

232
 atomic charge difference should correlated well with BOD. This descriptor is
known as superdelocalizability and was found to correlate well with BOD. The
correlations proposed for different alcohols as a test case are given below

BOD = 0.930 x 0.1 SE - 3.163, n = 19, r = 0.962 (13)

where SE is the electrophilic superdelocalizability.

Superdelocalizability is a measure of the reactivity of an atomic center and
hence it was suggested that the carbon atom to which the active functional groups
are attached is the active center. Since the reactivity of a particular atomic center
must relate the initial degradation step, it was suggested that the initial degradation
step is rate controlling.
The group contribution descriptors for functional groups developed by Desai
et al. 23 shown in Table 3 have been applied to a variety of different organic
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chemicals. The results shown in Table 4 indicate that this method has promise
and may be developed further.

TABLE 4
Comparison of Actual and Predicted In (k)

Experiment Predicted Erroi

Compound ln(*) In(fc) (%)

o-Cresol -2.6878 -2.9501 9.75

m-Cresol -2.3694 -2.9501 24.50
p-Creso\ -2.4647 -2.9501 19.70
Phenol -3.0006 -3.1509 5.00
2,4-Dimethylphenol -2.8460 -2.7439 -3.39
2-Butanone -3.1326 -2.9402 4.84
Acetone -3.1161 -3.2407 4.00
Butylbenzene -3.1285 -2.9402 -6.02
1-Phenylhexane -3.3971 -3.0278 -10.87
Aniline -3.1236 -2.9074 -6.92
Benzoic acid -2.1628 -2.7552 27.39

V. CONCLUSIONS

SARs are emerging as a valuable tool in predicting the toxicity and environ-
mental fate of pollutants. Because of the costly and time-consuming nature of
the testing methods, SARs are being effectively used by regulatory agencies in
the licensing of the manufacture of new chemicals as well as the setting of
standards for existing pollutants in the environment.
However, for a number of reasons, the application of SARs in the prediction
of biodegradability of environmental chemicals has only been evaluated in recent
times. The development of quantitative relationships between molecular char-
acteristics and biological activity requires a large and self-consistent data base.

233
 Unfortunately, most of the biodgradation data available in the literature have
been obtained by a variety of experimental methods which do not readily lead
to a consistent data base. Hence, the grouping of existing data into a large and
consistent data base is not yet possible.
Similarly, development of good correlations between molecular structure and
biodegradability depends upon the availability of suitable descriptors for a given
data set of consistent quality. Despite the fact that a large number of descriptors
are reported in the literature, most of them cannot be used for compounds having
a wide range of structural features. Even though log Kow has been used as a
descriptor for the development of SARs, most of the compounds involved belong
to congeneric groups which are not structurally diverse. However, log Kw can
be used in conjunction with other parameters such as substituent constants to
account for the structural diversity factors. On the other hand, topological de-
scriptors can account for the presence of various substituent groups by providing
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numerical descriptors. However, these descriptors cannot explain electronic effects.

The advent of sophisticated computing techniques for calculating some of the
parameters at the atomic level, e.g., atomic charge, electronic energy, and su-
perdelocalizability, has increased the potential for the development of SARs.
These descriptors have been used successfully in the development of SARs and
their potential utility is that a single descriptor may account for different substituent
groups and positions in the molecules without the need for additional parameters.
In fact, some relationships have been produced where a linear regression for a
wide class of structurally diverse compounds has utilized a single descriptor.
However, further research is required for understanding the mechanisms by which
biodgradation is related to these descriptors. Future efforts on the development
of SARs should be directed toward setting up large and consistent data bases as
well as generating more descriptors of the quantum chemical type.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the financial support provided by the

Australian Research Council for carrying out this study.

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