Human Toxicology of Chemical Mixtures. Toxic consequences Beyond the impact of One-Component Product and Environmental Exposures

575 Pages·2008·3.655 MB·English

by  Harold I. Zeliger (Auth.)

Preface
I have been a chemical toxicologist for almost forty years. As such, I
have studied and evaluated the toxicities of chemicals and the health effects
produced by human exposure to chemical products and environmental
chemicals.
This book really began over thirty years ago, when I was confronted
with the fi rst of scores of instances where individuals exposed to chemical
mixtures subsequently developed symptoms and effects which could not
be explained by the known toxicological effects of the individual chemical
species. In some instances, these exposures led to effects far in excess of
what would be expected from the exposure. In others, effects were noted
following exposures to extremely low levels of chemicals and in still oth-
ers the body organs targeted were not those known to be impacted by the
individual chemicals. Stymied, I advised people to look for other causes of
the conditions observed. These inquiries, however, led to my research into
the area of toxic effects of chemical mixtures and ultimately to this book.
As time progressed, I began to think that the noted effects might in some
way be related to the mixtures, but an explanation remained elusive. The
breakthrough came while I was simultaneously investigating two separate,
unrelated exposures. The fi rst involved the exposures of several people to
very low levels of herbicides and their carrier solvents that entered a build-
ing with air conditioning uptake air. The second involved the exposure of
an individual to chemicals off-gassing from newly installed carpeting in a
home. In both instances, air sampling revealed airborne concentrations of
all individual volatile chemicals to be less than ten percent of the values
known to affect people. Both exposures were to complex mixtures of
chemicals and both exposures led to effects unknown for the individual
chemical species.
These cases led me to hypothesize that exposures to chemical mixtures
could produce “strange” effects. A review of the literature revealed many
examples of unexplained health effects on humans following exposures
to mixtures. A study of these showed that in every unexplained instance
the mixture contained at least one lipophilic (fat soluble) and one hydro-
philic (water soluble) chemical. The literature showed that all body tissues
have lipophilic barriers surrounding them. This suggested that absorption
of lipophilic chemicals should occur more easily than for hydrophilic
species. This too was confi rmed by the literature and it was then hypothe-
sized that lipophiles facilitate the absorption of admixed hydrophiles.
xxi
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xxii PREFACE
Accordingly, a greater quantity of a hydrophilic species would be absorbed
if it were dissolved in a lipophile than would be taken up if the hydrophile
were present alone. This, too, was confi rmed by the literature. For exam-
ple, lipophiles are commonly used to facilitate the absorption of hydro-
philic pharmaceuticals. It was further hypothesized that greater absorption
of hydrophiles might account for the enhanced low level effects observed.
What was not predicted at the time was the observed attack of lipophile/
hydrophile mixtures on new target organs. In multiple cases, however,
human exposures to mixtures of lipophiles and hydrophiles showed attacks
at organs not known to be targeted by the individual chemicals.
It was found that all bodily systems are affected by some lipophile/
hydophile mixtures. These include: the reproductive (infertility), nervous,
digestive, skin, musculoskeletal, fi ltering organ, digestive, respiratory, car-
diovascular, immunological, and endocrine systems. A developing fetus or
young child (with an incompletely developed immune system) is particu-
larly vulnerable to attack by chemical mixtures.
The sources of lipophilic/hydrophilic chemical exposure include: envi-
ronmental pollution (air, water, and soil contamination), pesticide, herbicide,
and fertilizer residues in foods and drinking water, excipients (non-active
additives such as colors, fl avors, rheological agents, etc,) in foods and
pharmaceuticals, industrial chemicals, household chemical products, per-
sonal care products, cosmetics, and environmentally synthesized chemi-
cals that are formed from reactions with released chemicals with each
other and with naturally present species.
The subject of this book is effects on humans. Animal studies are
occ asionally cited, but conclusions are drawn primarily from the human
experience.
This book is divided into four parts:
Part I contains an introduction, a discussion of chemical toxicology and
mechanisms of chemical absorption and of interaction with various body
tissues on macro and molecular levels. Also discussed are the body’s pro-
tective responses to xenobiotic intrusion, including metabolism, immune
system, and endocrine system actions.
Part II discusses where the exposures to chemical mixtures come from,
including chemical product and environmental sources. Included are: air
pollution, water pollution, foods, chemicals used in food production, phar-
maceutical products, and electromagnetic radiation.
Part III examines the specifi c effects of mixtures on different body sys-
tems and organs and addresses predicting what the effects of uncharacter-
ized mixtures will be. Case studies of specifi c effects of chemical mixtures
on humans are listed and described.
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PREFACE xxiii
Part IV is devoted to regulatory requirements for toxic chemical warn-
ings for chemicals and chemical products and the need to adjust recom-
mended exposure levels for products containing chemical mixtures. This
part also contains suggestions for limiting mixture exposures in the prod-
ucts we use and recommendations for limiting environmental exposures to
toxic chemical mixtures.
I wish to acknowledge the encouragement of my children and their
spouses: David, Jennifer, Joseph, Christine, Michael, Katie, Laura and
Jeremy, during the research and writing of this book. David and Jennifer, I
can’t thank you enough for your critical review. Your scientifi c focus, intel-
lect, and rigor were invaluable. Jeremy, thank you for your editing and
computer skills. These helped immeasurably in the writing of this book.
This book is dedicated to my children and grandchildren as well as to
yours and those of everyone else with the hope that they will all live in a
healthier world.
Harold I. Zeliger
West Charlton, New York
April 2008
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1 Introduction
What do Gulf War Syndrome, Katrina Cough, Aerospace Syndrome,
and epidemic increases in the incidence of autism, Attention Defi cit
Hyperactivity Disorder (ADHD), birth defects, a sthma, mailroom illness,
s pontaneous abortion, and many cancers have in common? Each of these
can be associated with a single causative agent, but each can also be
associated with environmental exposure to chemical mixtures that do not
contain any of the known causative agents.
N o doubt some of the increased number of diagnoses being made for
environmentally induced illnesses (such as asthma and ADHD) are due to
improved methods of detection and reporting. The huge increases observed,
however, cannot be accounted for by increased diligence only.
Many environmentally induced illnesses can be attributed to exposures
to single chemical compounds. These have been and continue to be exten-
sively studied and numerous references address them. [ 1,2] Table 1.1
lists a few examples of single chemicals and the effects they are known to
cause.
Single chemical effects are not specifi cally addressed here. Rather, the
focus here is on illnesses that ensue following exposures to mixtures of
chemicals that cannot be attributed to any one component of an exposure
mixture.
Traditionally and historically, toxicologists have addressed the effects
of single chemicals. There are thousands of unnatural chemicals in our
environment, in our homes, and at our work place, and new ones are being
constantly added. It is virtually impossible for a person to be exposed to a
Table 1.1 Single Chemicals and the Effects They Are Known to Cause
Chemical Illness
Benzene Leukemia
Bromoform Spontaneous abortion
DDT Liver and kidney damage
Dibenzofuran Skin rashes and pigmentation
changes
n -hexane Central nervous system damage
Methyl mercuric chloride Irreversible brain damage
Trimellitic anhydride Asthma
3
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4 INTRODUCTION TO CHEMICAL TOXICOLOGY OF MIXTURES
single chemical. The unborn fetus is exposed to numerous chemicals
in utero, and babies have been shown to be born with hundreds of synthetic
chemicals in their blood streams. Nursing babies ingest large numbers of
environmental toxins found in mother ’ s milk.
As used here, an unnatural chemical is one that is either synthesized by
man and unknown in nature (e.g., PCBs, DDT, and toluene diisocyanate)
or one that is known in nature but is introduced in concentrations that are
much greater than those found in unpolluted environments (e.g., o zone,
1 ,3-butadiene, and a sbestos). We all drink water, breathe air, and eat food
that contains hundreds if not thousands of unnatural chemical compounds.
Household cleaning and maintenance products, adhesives, paints, disin-
fectants, and p esticides are just some of the sources of chemical mixtures.
Lesser known ones include disposable diapers, marking pens, air freshen-
ers, fragrance products, mattress covers, pharmaceuticals, food fl avors and
colors, and chemicals inadvertently carried home on the clothing of work-
ers. Naturally occurring phenomena such as fi res, petroleum seepage, and
volcanoes are also sources of chemical mixtures. The interaction of elec-
tromagnetic radiation with chemicals and the reaction of chemicals with
other released or naturally occurring chemicals produce still more mixtures.
Exposure to industrial chemicals impacts very large numbers of people
with wide varieties of single species and chemical mixtures.
B efore 1828, it was believed that organic chemicals could only be
formed under the infl uence of the Vital Force in the bodies of animals and
plants. Vital Force, also referred to as Vital Spark or energy and soul, is a
tradition in all cultures, including Eastern as well as Western ones. Until
1828, this vitalism, and only it, was believed to be responsible for all fac-
tors affecting life, including the synthesis of all organic molecules. It was
inconceivable that man could create such a material. In 1828, Friedrich
Wohler accomplished the fi rst synthesis of urea, a naturally occurring
component of human urine. Once it was demonstrated that such synthesis
was possible, chemists were free to pursue other such work, and since
then, many other naturally occurring compounds have been synthetically
prepared. Organic synthesis, however, has not limited itself to duplicating
nature. Hundreds of thousands of new, previously unknown to nature,
chemicals have been synthesized.
E ach new chemical added to our environment potentially creates a vast
number of new chemical mixtures with unknown health consequences.
The number of compounds is multiplied by the chemical reactions of
newly released compounds with existing released compounds as well as with
naturally occurring species to create yet more toxic molecules. Continual
exposure to electromagnetic radiation promotes further chemical reactivity
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1: INTRODUCTION 5
and results in the creation of still more toxins. There are no meaningful
experiments than can be done because the scope of the problem is unde-
fi ned. The Earth ’ s fl ora and fauna, including humans, are guinea pigs who
are affl icted by these toxicants and often do not understand the causes of
the resulting ailments. The results of these multiple exposures often only
become evident after people are stricken. Research into the toxic effects of
single chemicals often produce confl icting results when investigators fail
to consider the presence of species other than the ones being studied. For
example, different effects have been reported following the inhalation of
formaldehyde when it was admixed with other chemicals. [ 3]
For single chemical exposures, we know that most individuals are affected
by very high concentrations. Individuals who are genetically predisposed
and/or have been previously sensitized react to lower concentrations of a
chemical. Effects at different concentration levels are, for the most part,
known and predictable, enabling proper precautions to be taken. [ 4]
E xposures to mixtures of chemicals produce effects that are, for the
most part, unknown and unpredictable. These are
1. enhanced effects
2. low level reactions
3. unpredicted points of attack.
An enhanced effect is defi ned as one where exposure to a chemical mix-
ture produces a reaction at a target organ that is anticipated for one of the
chemicals in the mixture but is a reaction that is far in excess of that antici-
pated from the toxicology of the individual chemical species.
A low level reaction is one where exposure to a mixture of chemicals in
which each chemical is present at a concentration far below that known to
produce a reaction does indeed impact a target organ that is known to be
affected by one of the chemicals.
An unpredicted point of attack reaction occurs when exposure to a mix-
ture of chemicals results in the attack on an organ not known to be impacted
by any of the individual chemicals in the mixture.
T he human body is a complex mixture of chemicals. We have evolved
and adapted over time to contacting, eating, drinking, and breathing the
chemicals naturally present in our environment. We are not always
prepared for the assault of “ u nknown” synthetic chemicals on our bodies.
The introduction of a foreign chemical species (x enobiotic) challenges
the body’ s natural defense mechanisms to defend against an unknown
challenger. The body responds by trying to metabolize the invader so that
it can be eliminated, and/or the body fi ghts it with its immune system.
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6 INTRODUCTION TO CHEMICAL TOXICOLOGY OF MIXTURES
Most people are thus able to defend themselves against foreign chemical
species. Mixtures, however, present a special challenge to the body ’ s natural
defenses. Often, one part of a mixture attacks a particular organ while a
second species attacks a component of the defense mechanism that is trying
to defend the body. This is explored in more detail in the later chapters.
Our inability to defend ourselves against new chemicals and mixtures
often results in epidemics of disease. For example, asthma, autism, i nfer-
tility, and many cancers affect different parts of the body and seemingly
have different etiologies. All, however, can be related to a combination of
genetic predisposition and environmental exposure to chemicals. All are
less prevalent where chemical exposures are lower, for example, in rural
areas. All have known single chemical exposure causes and they can all be
related to low level exposure to chemical mixtures. The toxic effects of
chemical mixtures are explored in the chapters that follow.
References
1. P ohanish RP (ed.) Sittig’s handbook of toxic and hazardous substances , 4th
ed., Noyes/William Andrew, Norwich, NY, 2002.
2. Sax NI, Lewis RJ, Sr. Dangerous properties of industrial materials , 7th ed.,
Van Nostrand Reinhold, New York, 1991.
3. Zeliger HI. Toxic effects of chemical mixtures. Arch Environ Health 2003;
58(1):23 – 29.
4. Rea WJ. Chemical sensitivity , vol. 1, Lewis, Boca Raton, FL, 1992.
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2 Health Effects of Exposures to
Chemical Mixtures
2.1 Traditional Toxicology
T raditionally, toxicologists have addressed the effects of chemical mix-
tures as being a dditive, a ntagonistic, p otentiated, or s ynergistic. [1] To these,
sequential effects are added here.
2.1.1 Additivity
A dditive effects occur when two or more substances with the same tox-
icity (i.e., attack the same organ) are present together. The total or additive
effect is the sum of the individual effects. Additive effects are observed
when mixtures consist of species that are similar, that is, act identically on
a target organ. Additive effects may be observed, for example, when a
mixture of two compounds, each below the n o observed effect level
(NOEL) produce a predicted toxic effect when the sum of their concentra-
tions is greater than the threshold level for toxic action.
Examples of chemical mixtures that produce additive effects are
1. n -hexane and methyl- n -butyl ketone ( peripheral neuropathy); [ 2]
2. t richloroethylene and tetrachloroethylene (liver and kidney
toxins); [ 3] and
3. toluene and xylene (brain function loss). [ 4]
2.1.2 Antagonism
A ntagonism occurs when two chemicals interfere with each other’ s
effect. The result is a reduction in the effect predicted for the individual
species. Antagonistic mixtures need not be structurally similar. One spe-
cies may stimulate the metabolism of a second one or somehow interfere
with its sorption. Antagonism can be considered the antithesis of syner-
gism (discussed later).
Examples of chemical mixtures that produce antagonisms and their
effects are
1. D DT and p arathion (DDT induces and parathion inhibits enzy-
matic activity); [ 5]
7
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8 INTRODUCTION TO CHEMICAL TOXICOLOGY OF MIXTURES
2. oxygen and carbon monoxide (oxygen competes with CO for
receptor sites); [ 6] and
3. toluene and b enzene (toluene inhibits benzene metabolism and
reduces its toxicity). [ 7]
2.1.3 Potentiation
A potentiated effect is observed when the effect of a chemical is
enhanced by the presence of one or more other compounds that are only
slightly active. One compound can potentiate a second one toxicologi-
cally, for example, by producing the same metabolites in the body.
Examples of chemicals mixtures that produce potentiated effects are
1. organophosphorothiolate esters potentiate m alathion (CNS); [8]
2. isopropanol potentiates carbon tetrachloride (liver); [ 9] and
3. m ethyl ethyl ketone potentiates n - hexane (CNS and peripheral
nervous system). [ 10]
2.1.4 Synergism
S ynergism is observed when the effect of exposure to a mixture is much
greater than or different from that expected from an additive effect. In such
instances, exposures to mixtures of chemicals that are substantially different
from each other induce responses not predicted by the known toxicology of
the individual chemical species. When synergistic effects are observed, one
of the chemicals in the mixture changes the body ’ s response in a quantitative
or qualitative way. A quantitative response results in a much greater response
than would be observed for an additive effect. A qualitative effect results in
the attack on a different target organ than is not predicted.
Examples of chemical mixtures that produce synergism and their effects
are
1. nitrate and aldicarb (immune, endocrine, and nervous system); [ 11]
2. carbon disulfi de and carbon tetrachloride, (nervous system); [12]
and
3. cigarette tar and nitric oxide (carcinogenic). [ 13]
2.2 Sequential Effects
S equential effects arise when one chemical is absorbed fi rst and the
second chemical is absorbed at a fi nite, but important, time thereafter,
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2: HEALTH EFFECTS OF EXPOSURES TO CHEMICAL MIXTURES 9
resulting in an effect not observed from exposure to either one of the single
chemicals. Examples of chemicals that demonstrate this effect are as
follows:
1. The administering of ethanol or acetone prior to administering
acetaminophen results in a marked increase in the hepatotoxicity
of acetaminophen (because of enzyme induction by ethanol). [ 14]
2. P retreatment with diethyl maleate increases toxicity of bromoben-
zene (because of depletion of glutathione by diethyl maleate). [15]
3. I ndividuals with hepatic injury, such as alcohol-induced cirrhosis,
experience greater hepatotoxic effects than those not so previ-
ously injured. [16]
T he toxic mixture examples just presented are only a small fraction of
those that are fully discussed and referenced in Parts 3 and 4 of this book.
2.3 Unexplained Effects of Mixtures
A s noted in the introduction, exposure to chemical mixtures can pro-
duce enhanced effects, low level reactions, and unpredicted points of
attack. The toxicological literature has reported these but until recently
was at a loss to offer an explanation. The following published studies are
illustrative of how toxicologists viewed the unexpected effects of expo-
sures to mixtures prior to 2003.
Alessio reviewed the literature and reported on the exposure of workers
to multiple solvents in the workplace. His study showed that exposures to
some solvent mixtures resulted in the inhibition of the metabolism of the
solvents, whereas exposures to other solvent mixtures enhanced the metabo-
lism of the solvents. [ 17] No explanations of the effects noted were offered.
Feron et al., studied the effects of mixtures administered at the no
observed adverse effect level (N OAEL) and the minimum observed adverse
effect level ( MOAEL). Evidence of an increased hazard was found when
combinations of chemicals were administered at the NOAEL of each of
the components, despite the fact that exposures to the individual chemicals
had no adverse effects. When mixtures were administered at the MOAEL
levels of the individual components, some severe adverse effects were
noted. [ 18]
Alexandersson et al. studied the effects of exposure of carpenters to
formaldehyde, t erpenes, and dust particles. The mean f ormaldehyde levels
were far below the threshold value. The terpenes levels were very low and
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