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

575 Pages·2008·3.655 MB·English
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Preview Human Toxicology of Chemical Mixtures. Toxic consequences Beyond the impact of One-Component Product and Environmental Exposures

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 ZZeelliiggeerr__PPrreelliimmss..iinndddd xxxxii 55//1166//22000088 1122::3333::2244 PPMM 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. ZZeelliiggeerr__PPrreelliimmss..iinndddd xxxxiiii 55//1166//22000088 1122::3333::2255 PPMM 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 ZZeelliiggeerr__PPrreelliimmss..iinndddd xxxxiiiiii 55//1166//22000088 1122::3333::2255 PPMM 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 ZZeelliiggeerr__CChh--0011..iinndddd 33 55//1166//22000088 1122::5511::5522 PPMM 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 ZZeelliiggeerr__CChh--0011..iinndddd 44 55//1166//22000088 1122::5511::5522 PPMM 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. ZZeelliiggeerr__CChh--0011..iinndddd 55 55//1166//22000088 1122::5511::5522 PPMM 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. ZZeelliiggeerr__CChh--0011..iinndddd 66 55//1166//22000088 1122::5511::5522 PPMM 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 ZZeelliiggeerr__CChh--0022..iinndddd 77 55//1166//22000088 1122::5511::3399 PPMM 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, ZZeelliiggeerr__CChh--0022..iinndddd 88 55//1166//22000088 1122::5511::3399 PPMM 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 ZZeelliiggeerr__CChh--0022..iinndddd 99 55//1166//22000088 1122::5511::3399 PPMM

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Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.