Vaccari D.A., Strom P.F., Alleman J.E. Environmental Biology for Engineers and Scientists

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Appendix A lists the values of physicochemical parameters described above for several

important toxic substances.

Besides describing how substances distribute themselves within an organism, physico-

chemical parameters are important in the distribution between organisms and their envir-

onment. Of particular signiﬁcance is the K

value. This is a good predictor of how

substances will distribute between the lipid tissues of aquatic organisms and the water

they live in. Since K

for hydrophobic organics is very large, lipid tissues of these

organisms often store concentrations of toxins far higher than is found in the environment.

This phenomenon is called bioaccumulation or bioconcentration.

Example 18.4 The aqueous solubility of Freon (CCl

) is 280 mg/L. If its concen-

tration in water were 0.25 mg/L, estimate the concentration in fatty tissues. Assume

that there is no elimination.

Answer The molar mass of Freon is 120.9 g/L. The solubility in molar units is

0:280 g=L

120:9g=mol

¼ 0:00232 mol=L

From equation (18.7),

¼ 10

0:7100:862 log c

¼ 10

0:7100:862 log ð0:00232Þ

¼ 10

2:98

¼ 959

The Freon concentration in the lipid phase can then be estimated by assuming that it parti-

tions according to the octanol–water partition coefﬁcient. Then, using equation (18.6) [or,

equivalently, equation (18.1)], we have

¼ K

¼ 959  0:25 mg=L ¼ 240 mg=L

Lipid storage prevents excretion or detoxiﬁcation of a compound, and this results in

another phenomenon, called biomagniﬁcation. In biomagniﬁcation, because animals

that eat others which have already bioconcentrated the toxics will receive a higher dose

of the toxin, the concentration of toxin increases toward the top of the food pyramid.

Thus, predators at high trophic levels will be most sensitive to the presence of toxins

that bioaccumulate. The K

is a good predictor of the tendency of a substance to bioac-

cumulate, bioconcentrate, or biomagnify. These concepts are discussed in more detail in

Section 18.7.

Adsorption is another type of partitioning. It is the transport of a solute from gas or

liquid to the surface of a solid, or to other interfaces, such as of membranes. Adsorbing

materials in the environment include soil, sediment, and suspended solids in air or water.

Adsorption can reduce the availability of compounds to organisms by tying them up, or it

can incr ease availability by serving as a contact mechanism. An example of the latter is

the role of atmospheric dust in carrying gaseous radon into lungs.

Two types of chemical equilibrium often need to be considered together with physico-

chemical equilibrium: acid–base reactions and complex formation. Th is is because their

equilibrium occurs fairly rapidly, so that any change in concentration of one reactant

causes rapid conversion to another form. The im portance of this is that different forms

may have different physicochemical and biological behaviors. For example, many organic

acids exist in both undis sociated (HA) and dissociated forms (H

and A



). However, the

738 FATE AND T RANSPORT OF TOXINS

anion, A



, tends to concentrate in the polar aqueous phase, whereas the undissociated

form, HA, is more likely to concentrate in lipid or gas phases.

The distribution of dissociated and undissociated forms as a function of pH was de-

veloped in equation (3.3), and Figure 3.3 shows how this distribution would appear for

acetic acid. You will recall that an acid is 50% dissociated when pH equals pK

, whereas

it will be mostly undissociated at lower pH, and mostly in the dissociated form at higher

pH. Table 18.1 shows the pK

values for several pollutants.

In the case of acetic acid, for example, the dissociated form will be essentially

insoluble in lipids and thus will not pass through plasma membranes. On the other

hand, the undissociated form will have greater solubility in lipids, and therefore a greater

ability to pass through them. As a result, the effective Henry’s constant, aqueous solubi-

lity, and octanol–water partition coefﬁcient will all vary with pH for organic acids and

bases. If the undissociated form has a phase equilibrium constant of K

and for the

dissociated form it is K

, equation (3.3) can be used to derive the effective equilibrium

constant, K

eff

 K

1 þ 10

pHpK

þ K

ð18:8Þ

In each equilibrium constant of equation (18.8), the aqueous concentration is in the deno-

minator. Each equilibrium constant can represent a Henry’s constant, an octanol–water

partition coefﬁcient, or a linear adsorption partition coefﬁcient.

Equation (18.8) can describe the variation of toxicity of many substances with pH. An

example is hydrogen cyanide, which has a pK

of 9.37. Both the undissociated and dis-

sociated forms are toxic to ﬁsh, but the former is about twice as toxic. Thus, the toxicity

decreases somewhat as pH increases in the area of the pK

TABLE 18.1 Acid and Base p-Dissociation Constants

for Several Toxic Pollutants

Compound pK

Hydrogen sulﬁde 6.99

Hypochlorous acid 9.40

Hydrogen cyanide (1) 9.21

Phenol 9.96

p-Chlorophenol 0.80

Pentachlorophenol (2) 4.75

Trichloroacetic (1) 0.52

Analine-H

(3) 10.87

Ammonium 9.26

Note that aniline and ammonium are given in protonated form.

These are organic bases that tend to be ionized at pH levels below

the pK

, as opposed to the organic acids, which are ionized

predominantly at pH levels above the pK

Source: (1) Petrucci et al. (2001); (2) Christodoulatos and

Mohiuddin (1996); (3) Austin Community College (2004).

PHYSICOCHEMICAL PROPERTIES

739

Example 18.5 Henry’s constant for undissociated hy drogen sulﬁde (H

S) is 0.0042 and

the pK

(for the ﬁrst dissociation) is 7.1. The dissociated form is nonvolatile. What is the

effective Henry’s constant of H

S at pH 7.5?

Answer Use equation (18.3) with K

¼ 0:0042 and K

¼ 0:00. Then

c;eff

c;H

 0:0

1 þ 10

pHpK

þ 0:0 ¼

0:0042

1 þ 10

7:57:1

¼ 0:0012

An important example is ammonia. Being basic, it ionizes as pH goes below a pK

value of 9.26. In ionized form it is relatively imperme able to cell membranes and is

much less toxic to ﬁsh. However, although only a small fraction is undissociated at low

pH, that fraction increases by a factor of about 10 for each pH unit of increase. For exam-

ple, at pH 6, 0.056% of the ammonia is undissociated, but at pH 7 it is 0.55%, and at pH 8

it is 5.3%. From pH 7 to 8 the 96-h LC

to rainbow trout goes from 80 to 20 mg/L NH

N, a four fold increase in toxicity.

Another kind of chemical interaction with physicochemical processes is the form-

ation of soluble complexes. A compl ex is a combination of two or more species in solu-

tion held together by physicochemical or ionic forces. A notable example is the metal

ions, many of which form complexes with hydroxide and carbonate species present in

natural water. Often, a variety of different complexes can form from a particular metal,

resulting in species of varying composition and ionic charge. For example, in computing

the solubility of copper in natural waters, it is necessary to account for the formation of

the following species:

2þ

; CuOH

; CuðOHÞ

; Cuð OHÞ



; Cuð OHÞ

2

; CuCO

; Cuð CO

2

All of these species tend to be in equilibrium with each other. At a given total copper

concentration, the relative amounts of these species will depend mostly on pH and

alkalinity. Each of these copper species may have different toxicities to an organism.

Therefore, it follows that the toxicity of copper to ﬁsh, for example, will depend on pH

and alkalinity. Many other ions complex with metals, including sulﬁde and phosphate.

Chloride and sulfate are signiﬁcant ligands at seawater concentrations. Metals also form

complexes with organic compounds, such as to electronegative atoms; p-bonds (which

make up the C



C bond), as in unsaturated fats or aromatics; or by forming salts of

carboxylic acids.

As a result of processe s such as dissociation or complexation, a chemical may be pre-

sent in a phase in more than one form. The partition coefﬁcient, however, only describes

the ratio of like species in the two phases. For example, in the case of acetic acid in water,

the partition coefﬁcient is only the ratio of undissociated acid concentrations. However,

when a phase is analyzed, it is typically the total concentration of all species , including

complexes and dissociated forms, which is measured. Therefore, the mea sured ratio of

total concentrations for the two phases is given a different name, the distribution coefﬁ-

cient. The partition coefﬁcient does not change with factors such as pH, but the distri-

bution coefﬁcient does, in the same manner as equation (18.8).

Since structure has such an important inﬂuence on toxic behavior of chemicals, efforts

have been made to empirically correlate structural characteristics, as well as the physico-

chemical properties, to toxic effects. The ability to predict the toxicity of substances

is useful because given the variety of chemicals and effects, it is not feasible to perform

740 FATE AND T RANSPORT OF TOXINS

all the possible tests. Furthermore, the ability to predict effects could even be applied to

chemicals that have not yet been synthesized or puriﬁed.

Such correlations are called quantitative structure–activity relationships (QSARs).

The QSAR method uses statistical techniques, especially multiple regression or discri-

minant analysis, to ﬁnd relationships between a variety of predictors and a single effect.

Regression is used to predict continuous variables, such as the dose lethal to 50% of orga-

nisms (the LD

value, described below). Discriminant analysis is more useful for

categorical (either/or) endpoints, such as carcinogenicity or skin irritation. Examples

of QSARs are the correlation between narcosi s and polarity, or the correlation between

toxicity and the side-chain length of organophosphate pesticides, as described in

Section 18.3.

Various types of predictors can be used. The most common are (1) physicochemical

properties, such as solubility or K

; (2) functional group descriptors; and (3) molecular

indices. Prediction of narcosis from polarity is an example of the ﬁrst type. Organopho-

sphate toxicity is an example of the second type.

The use of functional groups is preferable to using properties, since it can be applied

even to never-synthesized chemicals in the proposal stage of a research project. On the

other hand, since the physi cochemical properties in some cases are directly related to

the toxic effect, they can provide better predictions. The functional group descriptors

typically go well beyond the kinds of groups listed in Table 3.4 . Also included are mole-

cular descriptors such as number of double bonds, number of rings indexed by type and

number of atoms forming the ring, and length of hydrocarbon chains.

Use of the third type of data, molecular indices, can be more powerful predictors of

toxic activity than functional groups. These include the molecular connectivity indices,

electronic charge distributions, and kappa environmental descrip tors. Molecular connec-

tivity indices (MCIs) are a group of parameters that describe the topological structure of a

chemical. It contains information on molecular size, shape, branching structure, cycliza-

tion, unsaturation, and heteroatom content (presence of atoms other than carbon in the

molecule’s ‘‘backbone’’). Physicochemi cal and biological parameters are correlated to

the MCIs in the same way as they might be correlated with the K

Despite the apparent promise of such predictors, they typically work well only when

limited to a single type of compound and a single toxic effect. For example, one might be

able to develop a model to predict the mutagenicity of polychlorinated biphenyls, but it

would be much more difﬁcult to develop a single model to predict the mutagenicity of all

chlorinated hydrocarbons. A single effect, such as mortality, may be a consequence of

different modes of action. Thus, a model to predict LD

might be limited to a particular

group of compounds. Jørgensen et al. (1997) describe the use of a variety of correlation

and QSAR techniques in the prediction of a variety of physicochemical and biological

parameters, including:

Aqueous solubility

Partition coefﬁcient (including K

)

Henry’s constant

Soil adsorption and exchange coefﬁcient

Rate constants for hydrolysis and photolysis

Enzyme inhibition

Microbial and mammalian toxicity (LC

,EC

, etc.)

PHYSICOCHEMICAL PROPERTIES 741

Uptake of organics by algae

Biosorption

Bioconcentration, bioaccumulation, and biomagniﬁcation factors

Biodegradation rate

No-effect concentration

Growth rate

Uptake rate, uptake efﬁciency, and excretion rate

18.2 UPTAKE MECHANISMS

Uptake is the transfer of a chemical from the environment into an organism. A toxic

substance must pass through a cell membrane to enter the organism. This can occur

naturally by several mechanisms, which were described in Section 4.1. Passive transport

occurs whenever there is a concentration gradient across the membrane. The situation is

illustrated in Figure 18.1.

The passive transport ﬂux, F

[Mt

1

L

2

], can be modeled in a simpliﬁed way as

being proportional to the concentration difference across the membrane by the diffusion

coefﬁcient, D, and inversely proportional to the membrane thickness, h:

ðC

 C

Þð18:9Þ

The diffusion coefﬁcient depends on the prope rties of the solute and of the membrane,

but in general, it is inversely related to the square root of the molar mass of the diffusing

species. Thus, small molecules diffuse faster. The concentrations at the faces of the plasma

lipid membrane can be assumed to be in equilibrium with the aqueous phases in which

they are in contact. Thus, C

¼ K

and C

¼ K

, where K

is the partition coefﬁ-

cient between the membrane and the adjacent phases. Substituting these relations into

Membrane

C = 0

Flux

Donor

Compartment

Receptor

Compartment

Figure 18.1 Passive transport across a membrane by molecular diffusion.

742

FATE AND TRANSP ORT OF TOXINS

equation (18.9), we can express the ﬂux in terms of the concentrations in the aqueous

phases:

ðC

 C

Þð18:10Þ

Thus, it can be seen that the partition coefﬁcient has a direct impact on the rate of trans-

port. Since the octanol–water partition coefﬁcient is a model for the lipid–water system,

compounds with a high K

will be absorbed easily by passive transport. The constants in

equation (18.10) can be lumped into a single parameter, the mass transfer coefﬁcient, k:

¼ k ðC

 C

Þð18:11Þ

The mass transfer coefﬁcient is an inverse measure of the resistance posed by the

membrane to movement of the substance. A similar equation can be used to describe

the transfer between two phases in the absence of a membrane, such as from air to water

or from blood plasma to a lipid phase. This is the ﬁlm theory model of interphase mass

transfer. The presence of two immiscible phases in contact with each other implies that

they will be physicochemically different and have different afﬁnities for the solute as

described by the partition coefﬁcient. The ﬂux of solute can be described similar to equa-

tion (18.11), but modifying the conce ntration of one of the phases by the partition coefﬁ-

cient, so that the ﬂux will be zero when the two phases are in equilibrium. For example,

the model for transfer from an organic phase with concentration C

to an aqueous phase

with concentration C

will be

F ¼ kðK

 C

Þð18:12Þ

In this case the mass transfer coefﬁcient, k, will depend on the diffusion coefﬁcients of

the solute in the two phases, as well as other factors, such as the amount of mixing

between the interface and the bulk ﬂuid.

Other transport mechanisms were described in Section 4.1. These include ﬁltration,

facilitated diffusion, active transport, and endocytosis. Facilitated diffusion and active

transport, which depend on a carrier in the membrane, have a maximum ﬂux associated

with saturation of the carrier. As a result, their dynamics can be described by a form of

Michaelis–Menten kinetics.

18.3 ABSORPTION AND ROUTES OF EXPOSURE

Absorption refers to uptake into the systemic circulation of an organism. Absorption

occurs through three main routes of exposure:

 Ingestion: absorption through the lining of the gastrointestinal tract from food or

other particles

 Inhalation: absorption through the lungs

 Dermal contact: absorption directly through the skin

Ingestion and inhalation are forms of intake . All three are mechanisms of uptake. The

route of exposure determines how much of a toxin enters and how different organs are

ABSORPTION AND ROUTES OF EXPOSURE 743

exposed. The toxicity of a substance depends on the route of exposure. For example,

arsenic is more carcinogenic by inhalation than by ingestion, whereas vinyl chloride is

the reverse. Asbestos danger from inhalation is well documented, but little evidence exists

yet for its toxicity by ingestion.

Uptake by ingestion occurs via absorption through cell membranes lining the gastro-

intestinal tract. Most of the surface area of the gastrointestinal (GI) tract is associated with

the villi of the small intestines. Thus, most neutral molecules will be absorbed there.

Organic acids and bases, on the other hand, depend on pH relationships for their absorp-

tion. The pH of the stomach ranges from 1 to 3, and the intestines from 5 to 8. Thus, weak

acids will be undissociated in the stomach and tend to be absorbed there. Conversely,

weak bases will be ionized in the stomach and therefore unable to pass membrane barriers

by passive transport. However, they can be absorbed in the intestines at the higher pH.

The pH relationships in the GI tract form a special mechanism for facilitating absorp-

tion of acids and bases. Because blood plasma has a pH close to neutral, weak acids will

be mostly dissociated in it, and only a small fraction will be in the undissociated form.

However, in the low pH environment of the stomach, weak acids will be mostly undis-

sociated. The undissociated form, being uncharged, can pass through the membranes of

the cells lining the stomach. After it crosses, it enters the bloodstream, where it become

ionized due to the high pH. This keeps the concentration gradient high, maximizing the

passive diffusion ﬂux.

Figure 18.2 illustrates what is occurring in the case of benzoic acid. The concentration

gradient of non-ionized acid is 100  1 ¼ 99. If the driving force were based on the total

concentration instead of the non-ionized concentration, the gradient would change sign

(101  2513 ¼2412). Benzoic acid would move from the blood into the stomach

instead of the reverse. A similar situation occurs in the intestines, except in that case

the pH of the lumen is higher than that of the blood. This facilitates absorption of

weak bases by a similar mechanism.

Ingestion does not only involve food. Risk assessment for contaminated land some-

times must take into account the ingestion of soil or other solids by children. A typical

assumption is that children eat 200 mg of soil per day.

The respiratory tract is the site of absorption by inhalati on for gases, such as

carbon monoxide, vapors of mercury, and high-vapor pressure liquids such as benzene

Membrane

Stomach

pH 2

Blood

pH 7.4

COO

−

COO

−

COOH

+ H

100

2512

Figure 18.2 How pH relationships in the stomach and blood plasma facilitate absorption of weak

acids such as benzoic acid.

744

FATE AND TRANSP ORT OF TOXINS

or perchloroethylene, as well as liquid aerosols and solid particles. Gas es and vapors are

absorbed by the large surface area of the alveoli. The absorptive ﬂux will be largely

controlled by the aqueous solubility of the solute. Very soluble gases and vapors, such

as chloroform, are quickly absorbed, and the rate of absorption is effectively controlled

by the respiration rate. Such compounds are said to be ventilation limited. The absorption

rate for less soluble gases and vapors is controlled by blood ﬂow to the lung. These

substances are thus said to be ﬂow limited. The absorption of ﬂow-limited toxins is also

affected by how completely the blood is cleared of the toxin as it passes through the

body before returning to the lungs. Toxins are removed from the blood in various ways,

including the storage of lipophilic substances in fatty tissue s and complexing of the

toxin with various receptors.

Particles larger than 10 mm tend to be trapped in the nose and expelled with muc us.

Particles smaller than about 0.01 mm remain effectively suspended in the airﬂow and

tend to be exhaled instead of affecting lung surfaces. Particles in the range between

these values tend to be deposited in various parts of the respiratory tract. The larger

ones are deposited in the upper respiratory tract, and then may be swallowed along

with mucus, entering the GI tract. Smaller particles go deeper, ﬁrst to the trachea or

bronchi. Some of these may be transported to the upper respiratory tract by the mucocilia-

ry escalator, and either be coughed up or swallowed. Others are engulfed by phagocytes

and absorbed by the lymphatic system. Particles smaller than 1 mm may reach the alveoli,

where they may be absorbed into the bloodstream. Particles of cigarette smoke range

between 0.1 and 1.0 mm, and most are between 0.2 to 0.25 mm. Thus, they tend to be

deposited in the tracheobronchial airways and alveoli.

Particles may be a source of solid toxins such as the heavy metals or polynuclear

aromatic hydrocarbons present in smoke. For example, cigarette smo ke is a source of

cadmium as well as PAHs, not to mention nicotine. Furthermore, regular smoking para-

lyzes the mucociliary escalator, which otherwise would help clear some of the particles

from the lungs. Particles may also help transport gases or vapors into the lungs by adsorb-

ing them. An example of this is radioactive radon, which otherwise is not very easily

absorbed. It has even been suggested that one reason that cigarette smoke is such a potent

cause of lung cancer is that it carries radon, naturally present in the air, into the lungs.

The human lungs contain about 70 m

of surface area for absorption. Adults breathe

about 8 L of air per minute at rest. For risk assessment purposes it is common to assume

a breathing rate of 20 m

/day (a bit less than 14 L/min). In aquatic organisms the gills

play a role similar to that of the lungs. Gills have been shown to absorb the pesticide

dieldrin, and cadmium was observed to be taken up by passive diffusion.

The stratum corneum is the main barrier to uptake of toxic substances through the skin.

Once past it, the epidermis offers little further resistance. The toxin then can enter the

dermis, from which it can be transported to other organs by the blood. Hair follicles offer

a diffusion shunt through the epidermis. Thus, the scalp and male face absorb toxins

more readily than other areas do. The palms have a thicker stratum corneum, but it is

relatively porous and thus is not a good barrier for toxins. Abrasion removes the stratum

corneum, greatly increasing absorption. Some solvents, such as dimethyl sulfoxide

(DMSO), can help carry toxins through the skin. This is taken advantage of in drug deli-

very by means of transdermal patches. Toxins that are absorbed but do not penetrate the

epidermis become washed away, since the epidermis replenishes itself about once a

month. The stratum corneum is replaced about every 14 days. It seems that all toxins

that can be absorbed by the skin do so by passive diffusion.

ABSORPTION AND ROUTES OF EXPOSURE 745

The skin can biotransfo rm substances, often increasing their toxicity. Repetitive

exposure to coal tar induces the enzyme arylhydrocarbon hydroxylase (AHH) in the

epidermis. This and other enzymes convert PAHs into more carcinogenic forms. It is inter-

esting that people with psoriasis cannot induce AHH and do not seem to develop skin

cancer upon exposure to coal tar.

Examples of toxins absorbed through the skin include hexane, carbon tetrachloride,

and some insecticides. Toxins can also be absorbed by the eyes, although in that case it

is the eye as a target organ that is usually of concern. Various invertebrates have been shown

to take up toxins through their body surface, including arthropods and crustaceans such as

Daphnia. Molting has been shown to be a way to shed heavy metals. In addition, other

routes of exposure are used experimentally, such as injection subcutaneously, intramuscu-

larly, or into bo dy cavities.

Often, the amount of uptake is reduced because some of the toxic substanc e is bonded,

complexed, or limited by diffusion in the environmental source. The fraction that is avail-

able for uptake is called the bioavailability. For example, a fraction of some pesticides

can become so strongly bound to soil particles that they are practically unavailable. It may

be necessary to take multiple routes of exposure into account for some toxins. A worker

applying pesticides by spray may absorb by both inhalation and dermal contact.

18.4 DISTRIBUTION AND STORAGE

Once a toxin enters the bloodstream, it is distributed rapidly throughout the body. How-

ever, organs do not all receive equal distributions, nor do they store them with equal

efﬁciency. Moreover, the location where most of a toxin is stored is not necessarily the

primary site of toxic effect. For example, 90% of the lead in adul t humans is stored in

the bones, but its effects are on the kidney, nervous system, and blood cell production.

Individual organs and tissues will then take toxins according to the blood ﬂow through

the organ (organ perfusion), their afﬁnity for the toxin, and the presence of any transport

barriers. Most capillaries have large pores between the cells that form their wall. In some

tissues, however, there are few or no pores. The most notable case is the blood–brain

barrier. This prevents passage of polar compounds of medium molar mass. Its behavior

is similar to that of an intact plasma membrane in that it is permeable to nonpolar com-

pounds. Thus, mercuric chloride, which is mainly in ionic form, does not penetrate,

whereas methyl mercury does. Other tissues have barriers as well, including the peripheral

nerves, the placenta, the eyes, and the testes.

The major sites of storage for toxins are (1) bound to plasma proteins, (2) the liver and

kidneys, and (3) adipose tissue. Plasma proteins form complexes with many toxicants,

serving to solubilize and transport them. The effect of protein binding depend s o n how

the proteins compete with processes that detoxify or excrete them. If they give up the

toxicants readily, they may help to transport them to the detoxiﬁcation site. If, on the

other hand, protein binding is relatively strong, it may sequester the toxins away from

detoxiﬁcation.

Toxins are often concentrated in the liver or kidneys, possibly due to their role in

detoxifying and excreting them. They contain their own binding proteins. An example

is metallothionein, which ﬁgures in cadmium storage and in the transfer of cadm ium

from the liver to the kidney. Toxins absorbed in the stomach and intestines must pass

through the liver before reaching other parts of the body, thus giving that organ a chance

746 FATE AND T RANSPORT OF TOXINS

to biotransform them. Toxins that have been inha led or absorbed dermally may reach

other tissues before the liver.

Adipose tissue (also called depot fat) is the tissue where energy is stored in lipid form.

The cells in these tissues contain droplets of triglycerides occupying more than 90% of the

cytoplasm. Naturally, they tend to concentrate hydrophobic toxins. Even nonhydrophobic

compounds can be stored in lipids after being conjugated with fatty acids. Toxins can be

stored in adipose tissue without causing harm there. However, lipid storage of toxins has

resulted in acute toxicity in humans who had stored subacute doses in their fatty tissues,

later liberating an acute dose to the blood by depleting their fats in a weight-loss program.

The bones also store some toxins, notably lead, radium, and ﬂuoride.

18.5 BIOTRANSFORMATION

Once inside an organism, many toxic compounds undergo chemical changes by biochemi-

cal reactions to form metabolites. Such biochemical changes are called biotransfor-

mation. Yet another distinction in types of toxicity is between those compounds that

react directly to cause damage and those in which metabolites are responsible for the

toxicity. In the former, biotransformation produces a reduction in toxicity; in the latter

it increases it. When biotransformation increases the toxicity of a chemical, the process

is called bioac tivation. Ultimately, biotransformation serves to produce more water-

soluble compounds that are more easily eliminated by the organism, or even to eliminate

them internally by mineralization to CO

and water. Chemicals that are not biotrans-

formed tend to be persistent in the environment.

An example of biotransformation increasing toxicity is sodium ﬂuoroacetate (rat

poison 1080), which is not extremely toxic itself. However, by the mechanism lethal

synthesis ﬂuoroacetate is converted to ﬂuorocitrate by the same Krebs cycle pathway

that converts acetate to citrate. The enzyme for the next step combines with the ﬂuoroci-

trate, but the reaction does not occur, and the ﬂuorocitrate does not easily desorb from the

active site of the enzyme. This amounts to reversible inhibition of the enzym e, which

slows the Krebs cycle to a crawl.

In vertebrates, much of the biotransformation is done by the liver. For example, metha-

nol is oxidized in the liver. The oxidation by-products cause the symptoms of methanol

poisoning, which include heada che, back and abdominal pain, blurry vision, and poten-

tially blindness. A latency period of 8 to 36 hours may precede the onset of symptoms as

oxidation products accumulate. Because ethanol is metabolized by the same pathway,

methanol poisoning can actually be treated with ethanol. The presence of ethanol slows

the oxidation of methanol by competing for the pathway.

Of course, many biotransformation reactions occur in other tissues; these are called

extrahepatic. Whether in the liver or not, biotransformations can be either catabolic

(breakdown reactions), such as oxidation, reduction, or hydrolysis, or they may be ana-

bolic (synthesis) reactions, which are called conjugations. The catabolic reactions are

also called phase I reactions. They usually expose or add a functional group such as

OH, NH

, SH, or COOH. Hydrophilicity is increased, but only slightly.

The anabolic reactions are called phase II, to indicate that they often follow phase I.

The phase II reactions involve congugating (combining) the substrate with another

molecule, such as an amino acid, or by adding sulfate, methyl, or acetyl groups. These

groups are added to the functional groups added in phase I. Phase II reactions greatly

increase hydrophilicity, speeding excretion of the compound.

BIOTRANSFORMATION 747