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CFS, MCS, LGS--the holistic approach

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Posted by Mike W on March 15, 1999 at 12:24:40:

Hello I have been monitoring this BB off and on for several months now.

I have Chronic Fatigue ( 9 years -- not one single day that I have felt good ) and Multiple Chemical Sensitivities. I react to almost anything with a scent.
Perfume, paint, exhaust, soap, etc etc...
I also have many other complaints --- memory loss, dizziness, vertigo, poor concentration, poor sleep, etc etc
(all the usuall symptoms that go along with these conditions)

I have read Dr.Stolls book (Twice!).
and am starting to do the skilled relaxation.
I am using an Alpha/Theta CD from the Relaxation Co. (The Brain Wave Pack ) Does anyone have experience with this CD ?

I am also :
taking steps to de-stress my life.
reading MAH/MAS.
going to do the rotation diet.

How do I know that I am actually reaching the required "state" when I do the SR ?

How do I know when the LG is gone ?

I checked into a Bio-feedback unit that was mentioned here
(under $100) and it is no longer available.

Any Suggestions as to what else I can do to heal ?

Thanks, Mike

Re: CFS, MCS, LGS, & SR. WOW !

Posted by JN on March 15, 1999 at 21:07:58:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

First call (800) 315 3010 and ask Belinda cobbs to give yo access for free to government data on research on the above.
Use searcgh engine and you will find the latest resarch on the cause and relation.
This is shocking how ignorant medical doctors are not following such research.
You may obtain instructions and authorisation thru E-mail:

Be specific in request for free access, and instruction about side.
This data is invaluable.
You may look at research of Miller, Meggs, Bell, Kippen, Rowan, it is the must.
Next I will not have to tell you to get mercury fillings from your jaws!
The data is overthere and there is no doubt it is correct!
next site is www.immed.gov

Re: CFS, MCS, LGS, & SR. WOW !

Posted by PART 1 on March 15, 1999 at 21:19:40:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

Integrated Defense System Overlaps as a Disease Model: With Examples for Multiple Chemical Sensitivity
Steven C. Rowat
Grantham's Landing, British Columbia, Canada
The central nervous, immune, and endocrine systems communicate through multiple common messengers. Over evolutionary time, what may be termed integrated defense system(s) (IDS) have developed to coordinate these communications for specific contexts; these include the stress response, acute-phase response, nonspecific immune response, immune response to antigen, kindling, tolerance, time-dependent sensitization, neurogenic switching, and traumatic dissociation (TD). These IDSs are described and their overlap is examined. Three models of disease production are generated: damage, in which IDSs function incorrectly; inadequate/inappropriate, in which IDS response is outstripped by a changing context; and evolving/learning, in which the IDS learned response to a context is deemed pathologic. Mechanisms of multiple chemical sensitivity (MCS) are developed from several IDS disease models. Model 1A is pesticide damage to the central nervous system, overlapping with body chemical burdens, TD, and chronic zinc deficiency; model 1B is benzene disruption of interleukin-1, overlapping with childhood developmental windows and hapten-antigenic spreading; and model 1C is autoimmunity to immunoglobulin-G (IgG), overlapping with spreading to other IgG-inducers, sudden spreading of inciters, and food-contaminating chemicals. Model 2A is chemical and stress overload, including comparison with the susceptibility/sensitization/triggering/spreading model; model 2B is genetic mercury allergy, overlapping with: heavy metals/zinc displacement and childhood/gestational mercury exposures; and model 3 is MCS as evolution and learning. Remarks are offered on current MCS research. Problems with clinical measurement are suggested on the basis of IDS models. Large-sample patient self-report epidemiology is described as an alternative or addition to clinical biomarker and animal testing. -- Environ Health Perspect 106(Suppl 1):85-109 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-1/85-109rowat/abstract.html
Key words: integrated defense system, multiple chemical sensitivity, disease model, IDS, MCS, traumatic dissociation, TD, pesticide, benzene, IL-1, vinyl chloride disease, autoimmune, overload, mercury allergy
Manuscript received at EHP 4 June 1997; accepted 9 October 1997.
Thanks to B. Bellin for research contributions and comments on the manuscript.
Address correspondence to Mr. S.C. Rowat, P.O. Box 175, 812 Port Mellon Highway, Grantham's Landing, British Columbia Canada V0N 1X0. Telephone: (604) 886-0670. Fax: (604) 886-0670. E-mail: steven_rowat@sunshine.net
Abbreviations used: ACTH, adrenocorticotropic hormone; APR, acute-phase response; BPD, borderline personality disorder; CNS, central nervous system; CRH, corticotropin-releasing hormone; d/p, direct or partial; EMU, environmental medical unit; GABA, -aminobutyric acid; GM-CSF, granulocyte-macrophage colony-stimulating factor; IDS, integrated defense system; Ig, immunoglobulin; IL, interleukin; IRA, immune response to antigen; MBP, mannan binding protein; MCS, multiple chemical sensitivity; MeHg, methyl mercury; MPD, multiple personality disorder; MT, metallothionen; NIR, nonspecific immune response; NK, natural killer; NS, neurogenic switching; OP, organophosphate; PCB, polychlorinated biphenyl; PTSD, post-traumatic stress disorder; SR, stress response; TD, traumatic dissociation; TDS, time-dependent sensitization; TNF-, tumor necrosis factor alpha; VIP, vasoactive intestinal peptide.
Integrated Defense System Overlaps as a Disease Model
Nervous, Immune, and Endocrine Integrated Defense Systems
Over past decades researchers have identified several context-specific response systems that are combinations of the central nervous, immune, and endocrine systems and their messengers. In this paper these are termed integrated defense systems (IDSs). The following IDS have been studied and reported in the literature: time-dependent sensitization (TDS), immune response to antigen (IRA), kindling, nonspecific immune response (NIR), acute-phase response (APR), stress response (SR), neurogenic switching (NS), tolerance, and traumatic dissociation (TD).
As Figure 1 illustrates neuroimmune-endocrine interactions of these IDSs are complex. There are homeostases within each of the central nervous, immune, and endocrine systems with multiple messengers running between them. Many of these messengers travel between two sets of the systems such as thymic peptides, adrenocorticotropic hormone (ACTH), tumor necrosis factor alpha (TNF-), and interleukins, or between all three such as -endorphins and interferons. This overlap indicates not only that any one IDS is likely to invoke wide systemic responses but also that overlaps and cross-interactions among the IDSs themselves are possible.

Figure 1. Messenger overlaps between the nervous, immune, and endocrine systems. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; TNF, tumor necrosis factor; VIP, vasoactive intestinal peptide. Figure 2. Overlaps in range of symptomatic response of nine IDSs across the nervous, immune, and endocrine systems.

Overlaps and Interactions among Integrated Defense Systems
Many IDSs are involved regularly in defense response. In exploring possible significant interactions among them, the following points can be made.
All IDSs have a range of known symptomatic response that extends across at least two of the nervous, endocrine, and immune systems, and several encompass all three. This is shown graphically in Figure 2.

Many of the IDSs use identical messengers, cells, and tissues to accomplish their responses (interleukin-1 [IL-1], interferons, ACTH, endorphins, T cells, substance P, neurotransmitters, etc.) Some known overlaps are collated into Table 1. (Also see "Range of Physical Action" in the individual IDS descriptions in the following section.) Because we are still discovering messengers at an appreciable rate [for instance, substance P (1) and the range of effect of the interleukins (2)], actual overlaps may be greater than we know at present.
Table 1.

Many IDSs have identical inciters (Table 1). For instance, eight of the nine IDSs are known to be incited by exogenous chemicals and six by microorganisms. There is either direct or partial evidence that all nine are induced by physical stress, seven by endogenous chemicals, seven by psychological stress, etc.

Many of the IDSs have a long time-range [for instance, months or years with TDS (3), TD, tolerance, kindling (4), and aspects of IRA (5)]. Temporally overlapping activity of several is therefore possible. With multiple or chronic stressors, some temporal overlap becomes inevitable.

Many IDSs are reported to operate through a threshold mechanism [TDS (3), kindling (4), SR (6), IRA (7)] and conceivably all do. In some cases a threshold is even fired by other IDSs in a chain reaction; for instance, the NIR can lead to the APR, which can lead to the SR.

Conditioning--associative learning--among the central nervous, immune, and endocrine systems has been documented and reviewed (8-10). For instance, selective immune parameters can be trained to change with central nervous system (CNS)-endocrine signals derived from taste (11), smell (12), audiovisual signals (13), and psychologic stress (8,14-16). CNS-endocrine emotions such as fear (17) can be conditioned to perceptions (sound, context), and CNS-endocrine symptoms such as anxiety, sleep disorders, irritability, and depression have been suggested to be classically conditioned responses to environmental odors (18).
The foregoing overlap data infer that there is strong potential for interactions between IDSs. For example Table 1 shows that there is direct or partial (d/p) evidence that psychological stress can incite seven of the nine IDS--TDS, IRA, NIR, SR, NS, tolerance, and TD. If we look at the ranges of physical action of these seven IDSs, we find that many are using the same messengers. For instance, all seven have d/p evidence of using IL-1, IL-2, T and B cells, and other immune cells; six have d/p evidence for using mast cells, TNF, other interleukins, Zn, and metallothionein; (MT); five have d/p evidence of using ACTH, -endorphins, immunoglobulins, and proteins of the classic or alternative pathways of the complement cytolysis system; four have d/p evidence of using limbic brain, cortex, peripheral nerve cells, dopamine and norepinephrine, substance P, vasoactive intestinal peptide (VIP), somatostatin, and other hormones, and three have d/p evidence of using other brain structures, serotonin and -aminobutyric acid (GABA), prostaglandins, and histamine.
If this overlap data is combined with the points listed above--the IDSs similarities in their range of symptomatic responses, the use of thresholds by the IDSs (some of which chain), long timeframes of certain IDSs, and conditioned learning, which cross-fertilizes inciters and triggering cues--there is potential for confounded activity among the IDSs that may include long-term learning of new thresholds of response. Such activity conceivably includes some existing diseases and syndromes. It may be especially useful to consider problematic diseases and syndromes like fibromyalgia, chronic fatigue, and multiple chemical sensitivity (MCS), which defy conventional analysis and often are postulated to be multifactorial conditions. Example models are generated for MCS in "MCS Mechanisms Generated from IDS Overlap Models."
IDS Disease Production Model Types
To narrow the vast list of IDS interactions we are faced with in Table 1, it may be useful to examine types of IDS disease production. If we posit a rapidly changing environmental context--a human immersed in levels of chemicals and stress that are outstripping the evolutionary time required originally to build the IDSs--we might see these three types of new interactions:
Damage to IDSs, in which one or more of the IDSs no longer functions correctly because of a physical distortion or loss of one of its parts and in which its/their interactions with the other IDSs are also crippled.

Inadequate or inappropriate response from IDSs, in which a radically changing context includes new inciters or new concentrations of known inciters that induce pathologically inadequate responses from one or more IDSs.

Evolving or learning IDSs, in which a changed context is mirrored by novel learning, including genetic learning, by one or more IDSs, giving rise to a new range of response.
When faced with a puzzling disease entity, we may then ask the following three questions about each IDS. Has the IDS been damaged? Has the context to which the IDS responds been changed so much that the IDS's range of response is no longer adequate? Has the IDS learned a new range of response to reflect a changed context?
Depending on the answers to these questions, we can build a combining hypothesis for the disease mechanism with several IDSs involved. This mechanism can include more than one type of IDS change. For instance (in a random example for illustration only): a) benzene can damage the immune response to antigen (19); b) continuous ambient air pollution such as NO2 produces a tolerance response, but with rising levels tolerance is eventually inadequate and is exhausted (20) and is followed by pathologic tissue changes; c) a child raised in an environment of severe abuse and neglect and without any caring adult support frequently will evolve a coping pattern that includes changes in, among other things, SR to aggressive situations, involving catecholamine, cortisol, serotonin, and endogenous opioid response changes (21).
If all three of these IDS changes were to occur in one person specific repeatable symptoms would be observed based on the interaction between the damaged IRA, the exhausted tolerance to NO2, and the modified (evolved) SR. If this specific constellation of IDS changes was to occur among a large number of people, reflecting a broad environmental context change in benzene concentration, NO2 concentration, and frequency of child abuse, then the resulting similarity of symptoms across separate patient case histories could be called a syndrome.
In this paper it is suggested that working backward from case histories using the IDS framework can in some instances reveal which IDS interactions cause the syndrome.
Individual IDS Descriptions
In "MCS Mechanisms Generated from IDS Overlap Models" MCS mechanisms are modeled as malfunctions and interactions of the nine IDSs. To accomplish this an understanding of the individual characteristics of IDSs is useful. Definitions drawn from the scientific literature, as well as a range of physical action, are given for each IDS. It is assumed that most readers will be familiar with most but not all the IDSs; therefore, more detail for each IDS, including a description of mode of action and inciters, is confined to the Appendix. Range of physical action and inciters are summarized in Table 1.
The full description of TD is included at the end of the listing below rather than in the Appendix, and readers are encouraged to examine it. The recent research into severe psychological trauma, including severe child abuse, has shown that it frequently produces permanent biological changes, and severe child abuse recently has been convincingly linked to well-known adult psychiatric dysfunctions. This background may be useful in understanding how TD could be an appreciable factor in widespread IDS interactions. The nine IDSs considered, along with referenced definitions and ranges of physical action, are listed below.
Time-Dependent Sensitization. "TDS refers to the ability of mild stressors--whether pharmacological or environmental--to induce physiological and behavioral effects which then progress, i.e., get stronger, entirely as a function of the passage of time since stressor presentation" (3).
"TDS is the progressive and persistent amplification of behavioral, neurochemical, endocrine, and/or immunological responses to repeated intermittent stimuli over time" (22).
The range of physical action includes neurotransmitters such as dopamine, norepinephrine, serotonin, GABA, and aspartate (3); hormones (corticosterone, ACTH, -endorphin); and immune system (3). Zinc is implicated in GABA (23-25) function.
Immune Response to Antigen. "The main feature that separates vertebrate from invertebrate immune systems is the ability to generate antigen-specific lymphoid cells" (26).
"[T]he immune system...learns to recognize foreign organisms and exhibits the property of memory. It remembers that it has seen a foreign organism and on its second encounter with that organism, it attacks more rapidly and more efficiently" (27).
The range of physical action for the IRA includes T- and B-cell receptors for specific antigens; thymus-directed T-cell growth processes including gene encoding for receptors (28); T- and B-cell multiplication; B-cell production of antigen-specific immunoglobulin antibody molecules including immunoglobulin (Ig)A, IgG, IgE, and IgM; T-cell production and reception of messengers including interleukins (IL-1 through IL-8). The range also includes TNF (2); platelet-activating factor (29); T- and B-cell production and reception of hormones including ACTH and -endorphin (30,31); T- and B-cell receptors for CNS messengers such as substance P (1,32), VIP (32,33), and somatostatin (32), and for endocrine hormones such as thymulin (34). Zinc is required for thymulin activation. For a review of dozens of messengers between the nervous and immune systems, see Plata-Salaman (29).
Kindling. "[K]indling refers to neural processes that mediate lasting changes in brain function in response to repeated, temporally spaced application of neurobehaviorally active agents" (35).
"Partial limbic kindling is a progressive and persistent lowering of the threshold for eliciting electrical after-discharges, but not motor seizures, in certain brain structures such as amygdala and hippocampus; behavioral consequences include increased avoidant behaviors" (22).
The range of physical action for kindling includes various brain structures, e.g., the cortex (36) and especially the limbic brain including the olfactory bulb and amygdala (37). Changes in brain chemistry are found, including a decrease in acetylcholinesterase enzyme activity that parallels the increase in sensitivity (37). Calcium-binding protein and tyrosine hydroxylase activity are reportedly reduced, and there are changes in -noradrenergic binding (36). Benzodiazepine receptor binding is modified (36), as are transmitter GABA and N-methyl-d-aspartate functions (4). Zinc may be implicated through GABA (23-25). Superoxide dismutase may also be involved (38). "These changes may be irreversible" (37).
Nonspecific Immune Response. "Long before the appearance of antigen-specific T cells or antibodies, the body is able to deploy an impressive array of humoral factors as a highly effective first line of defense against potential pathogens" (39).
The range of physical action for NIR includes circulating mast, natural killer (NK), macrophage, B, and T cells and their produced molecules such as TNF-, IL-1 through IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) (40) and histamine (1). Other actions include collectins such as mannan binding protein (MBP), surfactant protein-A, and surfactant protein-D (39); and complement components such as C1r, C1s, C4, and C2 (39) which are serum proteins that respond to antigen-antibody complexes (primarily) by generating an enzyme cascade that effects the membrane attack complex for cytolysis.
Acute-phase Response. "In the aftermath of injury, trauma or infection of a tissue, a complex series of reactions are executed by the host in an effort to prevent ongoing tissue damage, isolate and destroy the infective organism and activate the repair processes that are necessary to return the organism to normal function" (41).
The range of physical action for APR includes circulating cells such as macrophages, monocytes, platelets, and mast cells; stromal and endothelial cells local to damage; cytokines such as IL-1, TNF, IL-6, and possibly IL-4 and IL-8; thromboxane A2, and prostaglandins I2, E2, D2, and F2. Also included are leukotrienes B4, C4, D4, and E4, bradykinin; ACTH; glucocorticoids including cortisol; -endorphin; Zn; MT; and many liver-mediated proteins such as glycoprotein, C-reactive protein, complement C3, fibrinogen, and antiproteases.
Stress Response. "Stressors are the disturbing forces or threats to homeostasis, and adaptive responses include physical or mental reactions that attempt to counteract the effects of the stressors or disturbing forces in order to re-establish homeostasis" (6).
The range of physical action for SR includes brain regions: hypothalamus, brain stem, limbic system, and cortex; pituitary gland, adrenal gland, corticotropin-releasing hormone (CRH), ACTH, -endorphins, glucocorticoids, adrenergic system, and catecholamines. It also includes immune cells (macrophages, T, B, and NK cells); cytokines IL-1, IL-2, IL-3, IL-6, TNF, prostaglandins including PGE2; adenosine monophosphate (42); tissue Zn (43,44), and brain Zn (45).
Neurogenic Switching. "Neurogenic switching is proposed to result when a sensory impulse from a site of activation is rerouted via the central nervous system to a distant location to produce neurogenic inflammation at the second location" (46).
The range of physical action for NS includes immune system mast, T, B, and other cells; CNS peripheral cells; cytokines such as IL-1 and IL-2 communicating with both CNS and immune cells; neuropeptides such as substance P, somatostatin, and VIP communicating with both CNS and immune cells. Various regions of the central CNS may be involved in processing information during switching. Immune memory (cells and genetic coding) may also be involved in encoding the switching (10).
Tolerance. "Adaptation and tolerance are defined ultimately in biochemical and biological adjustments that enable organisms to survive...[T]olerance is characterized, not only by repair, but also by the development of refractoriness or immunity to the persistent insult so that repair at the [same] level is no longer required in the usual sense..." (20).
"Symptoms of exposure to many chemicals, whether inhaled or ingested, appear to follow a biphasic pattern. Adaptation is characterized by acclimatization (habituation, tolerance) with repeated exposures that result in a masking of symptoms" (47).
"The stage of resistance represents the sum of all nonspecific systemic reactions elicited by prolonged exposure to stimuli to which the organism has acquired adaptation as a result of continuous exposure. It is characterized by an increased resistance to the particular agent to which the body is exposed and a decreased resistance to other types of stress" (48).
"Oral tolerance is a term used to indicate antigen-specific systemic hyporesponsiveness after prior enteral (oral) exposure to that antigen" (49).
The range of physical action for tolerance includes multiple tolerance instances, mechanisms, and symptoms involving multiple organ systems (7,20,47-55); the entire nervous, immune, and endocrine systems are potentially involved.
Traumatic Dissociation. "Dissociation is defined in DSM-III-R [Diagnostic and Statistical Manual, 3rd Ed., Revised] as a disturbance or alteration in the normally integrative functions of identity, memory, or consciousness....a more precise definition of dissociation is required..." (56).
"Dissociation is one of the principal mechanisms by which people cope with overwhelming experiences. Dissociation terminates states of extreme physical and emotional arousal during the trauma, but over time dissociative processes may be activated by minor stresses and simple reminders of earlier trauma" (21).
"Dissociative states, used defensively at the time of abuse, may become a generalized defense in any situation where strong affect is aroused" (57).
"Dissociation may belong to the realm of biological mechanisms that are triggered by overwhelming trauma-related affects and events...." (58).
Current research and reviews assert that mild dissociation experiences are common in the general population (56) and that strong dissociation is a key and possibly defining component of post-traumatic stress disorder (PTSD) (21,59-62), borderline personality disorder (BPD) (57,58,60), and multiple personality disorder (MPD) cases (63). All these clinical psychopathologies are associated principally with childhood abuse (21,57-60,63-66) and their differences may represent stages and facets of the same underlying process (61,62,67,68).
Since the etiologies of PTSD, BPD, and MPD are only now being revealed and because they appear to overlap significantly (all three commonly involve child sexual abuse), TD as introduced here is modeled after dissociation as used by van der Kolk and Fisler (21,61,69) and others in which it refers to a combined biological-psychological mechanism central to all cases of PTSD, BPD, and MPD, and which also occurs in less extreme forms in nonpathologic populations.
TD, then, is an emergency defense system invoked during overwhelming inescapable psychological trauma, and modulates both cerebral logical organization and physiological affect regulation. Especially after chronic trauma in childhood, TD produces lasting changes in both, although the symptoms may not appear simultaneously.
MODE OFACTION. Recent articles in attachment theory (59,70), a research and theoretical framework in developmental psychology, describe the building of a conceptual model of relationships in the infant mind as early as the end of the first year of life (70). Attachment researchers have identified several types of children with incomplete or deviant attachment behavior (called avoidant, resistant, and disorganized behavior). They have found these types of children to be the result of insensitive, inconsistent, and abusive parenting, respectively (59,70). These children are postulated to have developed incomplete or damaged internal models of themselves and their relationships to the outside world (70), possibly permanently, because abused children are known to more frequently become abusing parents (70).
Working from a framework of adult PTSD and BPD, van der Kolk and Fisler (21) postulated disrupted attachment (including that resulting from abuse) results in a biochemically based loss of conceptual control. Current perceptions that appear superficially similar to past trauma cause emotion-based fight or flight responses to occur immediately, without the mediation of an abstract internal model that could decide whether such responses are valid. van der Kolk and Fisler further maintain that "forty years of research on nonhuman primates have firmly established that...disruptions of attachment early in the life cycle (as occurs in child abuse) have long-term effects on the neurochemical response to subsequent stress, including the magnitude of the catecholamine response and the duration and extent of the cortisol response. There are also long-term effects on a number of other biological systems, such as the serotonin and endogenous opioid system" (21).
In humans as well, PTSD, BPD, and MPD have been associated with lasting biologic changes in either baseline levels or during response to stress. For PTSD measured in war veterans, this includes norepinephrine, cortisol, ACTH response to CRH, serotonin (71), endogenous opioids, lymphocyte glucocorticoid receptors (21,69), and regional brain-flow patterns (72). A serotonin function review has cited its low levels in BPD and shown low levels of serotonin to be related to hyperirritability, hyperexcitability, and hypersensitivity, pain sensitivity, and lack of an inhibitory response in behavioral systems subserved by the hippocampal/amygdala system, including conceptual processing of reward, punishment, and uncertainty (73).
MPD was only recently recognized as an intentionally secret condition and not as rare as had been thought (perhaps not rare at all). MPD may be a superordinate diagnosis that may contain any of the symptoms of PTSD, BPD, and other personality disorders (63). In MPD separate personalities may have different (allergic) immune reactions (65) as well as differing responses to the same substance (alcohol, foods, and medications) (65), different body temperature, heart rate, and skin temperature (66), different eye muscle malfunctions (visual acuity problems) (66) and insulin levels (74), different handednesses (65), and different brain wave patterns (66). Thus in extreme cases of TD (i.e., MPD), not only is there an altered response to stress, there is an altered psychologic and physiologic response to almost everything. The number of varying personalities, which can approach 200 (74), has been significantly connected (p<0.0001) to the number of types of childhood trauma reported in a patient's history (65).
Thus overwhelming trauma, particularly in inescapable (61,75) or double-bind situations [such as abuse by father or other primary caregiver (76)], appears to make a conceptual shift or dissociation in how both the psychologic and physiologic systems respond to stress. When the trauma occurs during the formation of a child's conceptual models, especially chronically, the shift is likely to be much more intense.
RANGE OFPHYSICALACTION. TD physical actions vary with the degree of dissociation; pathologically in PTSD and BPD they include many, and perhaps all, brain, endocrine, and immune systems that are involved in the SR such as cortisol, CRH, ACTH, norepinephrine, and lymphocytes; serotonin and possibly GABA and other parts of the noradrenergic system; and endogenous opioids. Although less well understood, TD also affects whatever higher-level brain centers subserve amnesia for self and place and for depersonalization and derealization experiences [such as not recognizing one's reflection in a mirror or looking at the world through a fog (56)]. In MPD the range of physical action includes all the foregoing plus whatever brain, immune, and endocrine areas and mediators are required to differentiate insulin levels, heart rate, skin temperature, allergic reactions, responses to foods and medications, eye acuity, handedness, and brain wave patterns. In other words, most if not all body systems are included.
INCITERS. TD inciters are primarily conceptual: inescapably traumatic (frightening) events; i.e., child physical and particularly sexual abuse, war, rape, torture, domestic violence (72), and natural disaster experiences (69).
MCS Mechanisms Generated from IDS Overlap Models
Multiple Chemical Sensitivity: A Working Definition
A population of patients has emerged that reports elevated responses to low levels of environmental chemicals and adverse reactions to foods. One working group has termed these patients people reporting chemical sensitivity (77). They appear to come from four population categories that have been well-characterized elsewhere (78). These categories are: industrial workers, workers in tight buildings, people in contaminated communities, and individuals with and without acute chemical exposure histories.
Deciding who has MCS is problematic; the recently begun search for MCS biomarkers so far has been inconclusive (79-82).

Re: CFS, MCS, LGS, & SR. WOW !

Posted by Part 2 on March 15, 1999 at 21:24:10:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by PART 1 on March 15, 1999 at 21:19:40:

MCS Mechanisms Generated from IDS Overlap Models
Multiple Chemical Sensitivity: A Working Definition
A population of patients has emerged that reports elevated responses to low levels of environmental chemicals and adverse reactions to foods. One working group has termed these patients people reporting chemical sensitivity (77). They appear to come from four population categories that have been well-characterized elsewhere (78). These categories are: industrial workers, workers in tight buildings, people in contaminated communities, and individuals with and without acute chemical exposure histories.
Deciding who has MCS is problematic; the recently begun search for MCS biomarkers so far has been inconclusive (79-82). However, in the literature and based on extensive clinical experience, working definitions have evolved; this paper will use one similar to that proposed by Miller (83) and Miller et al. (84), with one notable difference: inclusion of the stress context.
Miller (83) proposes that MCS can be confirmed when, in a clean environmental medical unit (EMU), the following conditions are true: a) when a subject simultaneously avoids all chemical, food, and drug incitants, remission of symptoms occurs (unmasking); b) a specific constellation of symptoms occurs with reintroduction of a particular incitant; c) symptoms resolve when the incitant is again avoided; and d) with reexposure to the same incitant, the same constellation of symptoms reoccurs, provided the challenge is conducted within an appropriate window of time.
Working within the IDS overlap framework provided in "Integrated Defense System Overlaps as a Disease Model," a problem with this definition is that a particular form of psychological stress may be integral to the combined IDS response. For example, if TD has modified the SR and thereby modified the thresholds of other IDSs that use the same messengers (as modeled in the examples that follow), the above definition could lead to the improper attribution of symptoms to MCS if a concurrent psychological triggering of the SR is necessary for the low-level chemical response to occur. Because it is probable such a stress is not provided by the EMU, no response is found and MCS is therefore invalidated as a causative factor. Yet the response occurs again when the patient is in his or her normal (psychologically stressed) environment. Conversely, the patient may find the EMU stressful to the degree that it is not possible to unmask the symptoms. Consider the following report of a 21-year old patient with PTSD (whose response to chemicals is not reported): "A lot of times I wake up at two, three o'clock in the morning and I'm having an anxiety attack before my eyes even get open. Sometimes it's that I'm dreaming, because that [clinic visit] is still going around in my head, even though it was six months ago. I'm really scared of this one doctor, and a lot of times he's in [the dream]...I hyperventilate, and I can't breathe, and I have stomach spasms, muscle spasms, and sometimes I throw up after it's over" (85).
Bell et al. (86) expressed similar concern for MCS testing protocols because animal work shows TDS sensitization in one environment does not replicate in a novel environment. To put it simply: context matters.
Thus it may be that in searching for an MCS definition and mechanism the attempt to isolate the patient from the context is premature; patients' reports of what is happening to them in their own words may be our best source of data for formulating hypotheses of what is occurring. At present the only widely available forms of these reports are a few extremely moving self-reports that have appeared in the scientific literature (87,88) or the popular press and, importantly, collated data from clinicians (89-93), including attempts by clinicians to define the condition [collated by Miller (90)].
This wealth of rich, awkward, and unfinished data and other published reports, along with my own experiences with people reporting chemical sensitivity, have been used to generate the IDS-overlap MCS models to follow.
IDS Overlap MCS Examples: Introduction and Summary
What appears to be required in the study of MCS--with its variable biomarkers, multiorgan symptoms, and diverse patient demographics--is a model that allows variable biomarkers and symptoms among different hosts, and even in the same host at different times. For instance, a review of immunologic data reported on MCS (94) notes many abnormalities; some of these, however, are in opposite directions: T-cell helper/suppressor ratios reduced in several studies but raised in another; unusual amounts of autoantibodies in some studies but not in others; reductions in absolute T-cell counts in some studies and increases in others. Elsewhere a study of immune marker alterations among several hundred workers at a computer factory exposed to various chemicals showed a split skew with significant increases or decreases in T-cell helper/suppressor ratios as well as autoimmune markers (95). Work with single-photon emission-computed tomography brain scanning of veterans with chemical sensitivities (96) shows differences during the triggering state; this suggests a coded response but there does not appear to be traceable damage to any system. The task then may not be to find a linear marker for MCS, but to understand and extract from the data more complex changes in mechanisms underlying the biomarkers.
The overlap and chaining of thresholds in the examples developed below are suggested as first attempts at models that include nonlinear interactions between linked homeostatic systems. Mathematically they probably would best be expressed by a set of linked differential equations, although the explicit mathematics are not presented here. [Mathematics might best be supplied by chaos theory, which has been used to develop a model of the immune system as a dynamic adaptation system (27,55) to model the coevolution of hosts and parasites (97,98) and to study pathology (99), psychology (100), physiology (101), and a large number of other biomedical disciplines (102-107)].
Examples of the following MCS models produced through IDS interaction will be considered in the balance of this paper. Some are included because parts of their mechanism have been directly suggested by the MCS clinical literature; others are included because they are known to be widespread phenomena and their IDS interactions appear capable of generating MCS symptoms.
Six models are considered separately; they are grouped as follows:
1. MCS attributable to damage of IDSs
1A. Pesticide damage to the CNS
1B. Benzene disruption of IL-1 maturation
1C. Autoimmunity to IgG or vinyl chloride disease

2. MCS attributable to inadequate or inappropriate response from IDSs
2A. Chemical and stress overload (using a combination of formaldehyde, air pollutants, anxiety, benzene, alkylphenol novolac resin, and anger)
2B. Mercury allergy in a genetic subset (to increased levels of mercury in dental applications, food, and paint)

3. MCS attributable to evolving or learning IDSs
3A. MCS as evolution (a semantic exploration)

IDS Overlap MCS Model 1A: Pesticide Damage to the CNS
Introduction. Pesticides, including chlorpyrifos, are widely implicated in case histories and clinical reports of MCS (89,91,108-112), both in terms of outbreaks of MCS after group exposures and of patient attributes of exposures that precipitated their condition.
Certain widely used pesticides that have disrupting effects on GABA neurotransmitters (4,75,113) may be initiators of kindling (4). This interference may also extend to polychlorinated biphenyls (PCBs) (75) and in general to organophosphate (OP) and organochlorine compounds (113). Some organochlorine insecticides such as chlorpyrifos reportedly cause both chronic neurologic symptoms (114) and modulation of the IRA (112). Certain OP insecticides enhance the large-fiber distal axonopathy caused by other OPs such as chlorpyrifos (109,114). Recently reported studies of Gulf War veterans confirm earlier reports of a connection between a syndrome of neurologic damage and wartime exposure to pesticides and insecticides (115-118).
Initial Damage. If we assume a relatively severe exposure to an OP such as chlorpyrifos with a coexposure to a synergistic damage-promoting solvent or other OP, there can be initial disruption of the GABA neurotransmission as well as damage to long nerve cells. It is also fair to assume that the nerve damage initially will invoke the NIR and, if the damage is sufficient, the APR.
Examining the IDS overlaps in Table 1, we see that the disruption of GABA may cause kindling and TDS to malfunction, as both use GABA. We also see that a large number of other messengers have been invoked by the NIR and the APR, including ILs, immune cells, ACTH, and -endorphin. ACTH and -endorphin, however, are also used by TDS. Because we are assuming that the GABA disruption also changed TDS, the situation is unstable. In one direction TDS may modify the APR through ACTH and -endorphin; in the other direction the APR may change TDS further, possibly including changing its threshold of reaction to incitants or the magnitude of its response. This bidirectional interaction is shown in Figure 3.

Figure 3. Modifications through overlap of messengers among IDSs. In multiple chemical sensitivity model 1A (pesticide damage to the CNS), TDS and APR are overlapping messengers ACTH, -endorphin, various hormones, metallothionein, zinc, and possibly others (Table 1). Such overlap provides opportunities for both intended and unintended bidirectional influences, including modification of triggering thresholds and changing the functions of messengers unique to each.

Extensions. With reference to Table 1, several major complications can be envisioned that would increase the chances of IDS interaction in this model; three will be discussed briefly.
BODYBURDENS ANDSYNERGIES OFTOXICCHEMICALS, INCLUDINGPESTICIDES. Various chemical contaminants such as dioxins, PCBs, insecticides, and pesticides are reported in human tissue at levels that arouse concern (119-125). Because several chemicals are known to be present simultaneously in the normal body burden (119,125), synergies may occur. Examples are carbon tetrachloride with chlordecone (126-128) and chlorpyrifos with other OP pesticides (109,114). This could mean continuous disruption of GABA and unstable action of ACTH and -endorphin, possibly leading to unanticipated threshold changes in the TDS of various chemicals.
PREEXISITINGTD. If a patient has a history of trauma sufficient to have modified his or her SR, psychological cues may incite changes in many messengers that also affect TDS, including dopamine and norepinephrine, ACTH, -endorphins, Zn, IL-1, and other interleukins, hormones, and cells. Such stress occurring concurrent with new chemical exposure could be the mechanism by which the response is spread (as explored in model 2A). At least one study has reported higher rates of self-reported childhood abuse among women reporting MCS than among controls (129), and it may be more than chance that a significantly higher proportion of females than males report MCS, as a similar female:male ratio occurs among those who are estimated to be sexually abused in childhood; about 4:1 in the former (130,131) and 3:1 in the latter (57).
EARLY ANDONGOINGZINCDEFICIENCY. Zinc deficiency has been widely investigated in the last two decades and is now recognized to be a public health problem (132); a recent estimate is that 30% of the adult U.S. population is at risk. Zinc is centrally involved in multiple human systems (133), including GABA and other neurotransmitter enabling (24,45,134-137), and in sequestering and defense against heavy metals and chemicals (138). Gestational Zn deficiency appears to damage hippocampal and other functions (44,45,139,140). Chronic Zn deficiency reduces the IRA by deactivation of thymulin (133,141-144). Thus several crossovers with TDS are possible. Limbic structures and GABA may be malfunctioning because of early Zn deficiency; or ongoing chronic Zn deficiency may, through lack of MT and increased infection and other malfunction of the immune response, modify TDS further, with crossovers at ILs, immunoglobulins, TNF, other immune cells, and ACTH and -endorphins.
Combining Extensions to Produce Variants of MCS. Given a base of a large number of people exposed to pesticides in our society, the logical combinations of these extensions with the initial exposure may generate symptomology, demographics, and incidence of MCS. That is, some exposed persons may already have body burdens of chemicals, some will have TD, and some will have Zn deficiency. Because all three conditions affect TDS, similar but not identical syndrome sets will be generated. Additionally some persons may have two of the three preconditions and a small set will have all three. These seven logical syndrome sets will share some characteristics but each will differ from the other six; each set will have a unique blend of incidence, intensity, and symptomology. A group of patients now clinically defined by one researcher as having MCS may constitute a particular skew of these seven sets, those defined by another a second skew, etc.
IDS Overlap MCS Model 1B: Benzene Disruption of IL-1 Maturation
Introduction. In a series of recent experiments on mice and human in vitro cells, benzene through its metabolites has been shown to prevent bone marrow cells from producing mature IL-1, and this is thought to play a central role in benzene-produced aplastic anemia (19,145-148). Combined with the immense amount of data on a large number of cancers and toxicities that benzene is known to cause (149-157) as well as its ubiquitousness in our environment, this makes it clear that we need to know more about its effect on IL-1 and possibly other cytokines, both in the bone marrow and in other body milieus. For instance various researchers have implicated benzene in human bronchial, colon, and liver damage, leukemia, DNA damage, tumors including brain, liver, stomach, and lung, cardiac abnormalities, eye irritation, drowsiness, unconsciousness, uncoordination, and heart attack (and in mice, birth defects and tumors). Benzene is present in gasoline (from auto exhaust, vehicle interiors, and gas stations), diesel exhaust, building materials, plastics, polypropylene food containers, cooked foods, printers, printed and copied paper, copy machines, incinerators, and tobacco, wood, and marijuana smoke.
IL-1 holds a central place in neuroimmune-endocrine response. According to reviews by Whitacre (2) and Plata-Salaman (29), IL-1 is produced by many cell types, some immunologic, some endocrine, and some in the CNS. IL-1 may be the central messenger in the SR (29), it has receptors in both immune and CNS tissue (158), including the brain (158), and it can cross the blood-brain barrier (159). Its effects include upregulation of IL-2, interferon, and other lymphokines; it acts as a chemoattractant for T and B cells, and it acts synergistically with IL-4 and IL-6. IL-1 also exerts effects on NK cells, regulates cell growth including both immune and nerve cells, promotes inflammation (prostaglandins), induces fever (160) and slow-wave sleep, increases levels of epinephrine and vasoactive intestinal peptide, induces synthesis and release of various pituitary hormones including ACTH, and enhances the release of -endorphin, as well as having other effects. Recent work on the evolutionary origins of IL-1 and the other key cytokines IL-2 and TNF- has shown them to be derived from invertebrate forms that perform similar jobs (161), and in light of recent evidence of various immune (26,161) and lectin (39,162-164) origins, it would appear that IL-1 holds central place in the first memory system, the nonspecific immune system, which predates even the existence of a CNS, much less a brain.
Along with the relatively new data about IL-1 suppression by benzene metabolites (19,145-148), benzene metabolites induce leukemia and other DNA damage (165-167). If this damage occurs at levels sufficient to invoke any of the eight IDSs besides kindling, IL-1 is likely to be involved as part of the IDS response; IL-1 is the single most shared messenger among the body's IDSs (Table 1).
One MCS study has shown IL-1 to be produced in significantly reduced amounts from peripheral blood mononuclear cells in cases relative to controls (81), although the authors state that this may have occurred because of laboratory methodology problems. Notwithstanding the slightness of this evidence, the IL-1-benzene connection appears to be a reasonable candidate for MCS investigation if the suppression of IL-1 maturation in bone marrow by benzene metabolites also holds in the large number of other sites where identical IL-1 is produced. It also may be noteworthy that the list of benzene-containing substances is close to being a list of the MCS substances most highly reacted to. If we suspect that which chemicals MCS sufferers react to may be a meaningful guide to what caused the condition, benzene is a good place at which to start investigating.
Initial Damage. If benzene metabolites have also downregulated the IL-1 an IDS is using for its messaging, the IDS response to benzene may be changed. For instance if we assume that benzene exposure induces the APR, then because of the benzene downregulation of IL-1, other messengers in the APR could have distorted values; these include ACTH, -endorphin, prostaglandins, other interleukins, mast cells, and other immune cells. TDS also uses ACTH and -endorphin; if it is invoked, its threshold of response may be modified. If the benzene exposure has been sufficient to induce the SR, then the distorted IL-1 values may additionally affect TDS through limbic brain structures and dopamine and norepinephrine, and kindling through these and through cortex and higher brain structures.
Extensions. CHILDHOODWINDOWEXPOSURES. Childhood exposure data indicate that if exposure to benzene (or benzene-derived chemicals that have similar metabolites) occurred during developmental windows, special damage or immune learning could occur. Gestational windows correlate a wide variety of fetal malformations, toxicities, and subsequent developmental problems with various pregnancy exposures to PCBs (168), antibiotics (169,170), anesthetics (171-173), and environmental chemicals (174-177). Infant developmental windows have been reported to correlate hexachlorophene washing with neonatal brain damage and death (178,179). Such exposures of benzenoid chemicals may induce a TDS to benzene or its derivatives or an IRA to a hapten formed from such a chemical or its metabolites.
HAPTENSPREADING FROMCONTINUOUSEXPOSURE. Antigenic haptens are formed from both aromatic and nonaromatic chemicals (180-184). An interesting series of experiments with acetaldehyde (183,185-189) has shown that the immune response successfully "...could be raised by immunizing with acetaldehyde conjugated to a carrier protein different from the one that is used for testing" (185). In other words the immune response could recognize the antigenic chemical segment and spread the reactivity to other carriers. In the case of acetaldehyde, usually IgE, and in one case IgG and IgM, is raised to acetaldehyde-protein adducts (183), and this has been used both in diagnosing alcoholism (186,187) and as an explanation for alcohol allergy (183). Benzene is the building block of the enormous number of new antibiotics, fuels, plastics, printing materials, food additives, pesticides, cleaners, and cosmetics that have been added to our environment in recent decades. If this immune recognition could happen with benzene metabolites or derivatives, the crossover between the IRA and another IDS, especially in light of the dysregulation of IL-1 by benzene, might account for both threshold response change and spreading found in MCS patients.
EARLY ANDONGOINGZINCDEFICIENCY. IL-1 and Zn-thymulin are synergistic. [Thymulin is central in T cell and other immune regulation (34) and Zn is required for thymulin function (142,190)]. IL-1 delivers Zn to thymulin via MT mRNA and Zn-thymulin potentiates IL-1 activation of nuclear protein kinase C in isolated splenocytes (191). Also, Zn deficiency in gestational and childhood windows, especially in conjunction with benzenoid environmental chemicals (192), reportedly causes a variety of malformations (44,193) including CNS development. Lack of Zn during early rat brain growth produces neurologic abnormalities (44,139,140). See additional discussion in section on model 1A.
BODYBURDENS ANDSYNERGIES OFTOXICCHEMICALS, INCLUDINGPESTICIDES. Almost all the chemicals commonly in the body burden are benzenoid. See detailed description in section on model 1A.
PREEXISITINGTD. In a human case-control study, psychological stress reduces the amount of IL-1 produced by peripheral blood leukocytes, which was correlated with the slowing of wound healing (194). See detailed description in section on model 1A.
Combining Extensions to Produce Variants of MCS. As discussed in the section on model 1A, these different situations can be combined to produce overlapping syndromes that could be subsets of MCS. Early window effects, hapten spreading, body burdens of benzenoid chemicals (and continuous exposure to benzene itself), preexisting TD, and Zn deficiency in early windows or later could interact individually with an IL-1 dysregulation model to increase or modify the effect. Any combination of two, three, four, or five of the extensions with the original could produce a different subset of symptoms and hence possibly appear as a different subset of the main syndrome.
IDS Overlap MCS Model 1C: (Vinyl Chloride Disease) Autoimmunity to IgG
Introduction. A fascinating variant of "Hapten Spreading from Continuous Exposure" is that it appears that immune system messengers themselves can become objects of immune response. This has been hypothesized as the central event in vinyl chloride disease (95,195-197), which may be a rheumatoidlike (198) autoimmunity to IgG after chronic vinyl chloride exposure damages the IgG molecule. Other chemicals that induce autoimmune disturbances include halothane (184) and acetaldehyde (183), and biomarkers and symptoms in such disturbances exhibit variable data in multiple organs (197), indicating that several effects on the IRA may be occurring. In addition, food lectins such as BanLec 1 (found in bananas) can be inciters of IgG; lectins also interfere with the complement NIR (162,199,200), commonly act as superantigens (54,162), and are endocytosed in relatively large quantities in the gut (200).
Initial Damage. In our model we assume that chronic exposure to vinyl chloride has damaged both IgG and other tissues and the IRA produces T-cell-mediated autoimmune complexes raised against these tissues (196). We do not know with certainty the memory mechanism of such autoimmune disturbances; possibly it involves DNA encoding in the variable (diversity) joining recombination of T cells (26,28,201,202). In addition T memory cells exist for long periods, decades at least, without any booster from antigens (5,203).
Extensions. SPREADING TOOTHERIGG-INDUCINGANTIGENS. Certain foods such as bananas, milk, and eggs produce unusually high levels of IgG allergic responses in pooled human blood (199). Soy (204), beef (205), and corn (206) also induce IgG, as do various chemicals (181,182,206). Suppose a subject consumes one of these substances and has an IgG reaction to it; by increasing the IgG level, the subject is simultaneously increasing the total autoimmune reaction to IgG itself. This may induce an additional IDS such as NIR to become involved.
Because the NIR is also known to induce the immunoglobulins, it becomes possible that a feedback loop will be set up: with more IgG comes more IRA and more NIR; with more NIR comes more IgG. This escalation could be sudden in certain conditions (like a painful audio feedback), and, by multiple crossover messengers, might induce the SR and TDS to the initiating foods or chemicals. In this way, a large number of IgG-provoking substances eventually could become inciters of a TDS response.
SUDDENSPREADING--MULTIPLEIDS SENSITIZATION TOIGG. This possibility, though apparently supported by no direct experimental evidence, produces such an interesting model that it must be at least mentioned briefly. What happens if after IgG becomes antigenic and IgG-inducing substances are introduced, a feedback loop causes TDS both to the inciting substance and to IgG? A spreading/multiplier effect is then set up. Any inciter of IgG automatically becomes an inciter also of TDS, even without a specific spreading event. The subject would suddenly become sensitized to all the foods and chemicals that already incite IgG, such as those mentioned in "Spreading to Other IgG-inducing Antigens." This type of quick spreading matches an important and puzzling aspect of the MCS syndrome.
FOOD-CONTAMINATINGCHEMICALS. The presence of pesticide residues, additives, and packaging migrants in commercial foods provides an opportunity for chronic or acute conditioned association between a chemical and an IgG-inciting food. Additionally, if such a chemical became complexed with the food before or during metabolism, the association would be different and possibly more antigenic. It is perhaps noteworthy that such complexing does not appear to have been studied; the literature on food contaminants (surprisingly sparse) deals largely with a few identified migrants and contaminants (207-216) rather than with their ability to complex with foods. The intense European Economic Community initiative to develop measurement and reporting techniques for packaging migrants is based on specific lists of chemicals (217,218); unfortunately complexing with foods is not included.
Combining Extensions to Produce Variants of MCS. Reports of autoimmune markers in MCS patients (like most MCS data) are inconsistent. A recent report (89) shows antismooth muscle antibodies in about half the patients seen in a clinical practice but no data about anti-IgG antibodies or antibodies against any other IDS messenger. Although many MCS patients report food sensitivities, this model has been presented chiefly as illustration. It is plausible that any IDS messenger that could act as an antigen could provide a feedback mechanism for spreading of the MCS response. An MCS so produced could be viewed as a form of chemically formed autoimmune disease.

Re: CFS, MCS, LGS, & SR. WOW !

Posted by Part 3 on March 15, 1999 at 21:26:03:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by Part 2 on March 15, 1999 at 21:24:10:

IDS Overlap MCS Model 2A: Chemical and Stress Overload
Introduction. In past decades the amounts and types of chemicals encountered indoors and outdoors in food and air have risen exponentially (78). Workplace environments contain chemicals at dangerous levels based on outdated threshold limit values that were never tested and are still in use because of corporate political pressure (219). Sealed office buildings built in the 1970s and 1980s use recycled air and have spawned outbreaks of a new syndrome, Sick Building Syndrome (220-223), which may be a subset of MCS (221,224). Neighborhoods have become car centered. Cars have become necessary for work and pleasure, and chemicals from car and diesel exhaust, incinerators, and wood smoke turn the air in populated areas into a toxic smog (225-229). Pollution inside average urban houses with synthetic rugs, cleaners, adhesives, paints, and petroleum heating systems has increased to the point where the levels of benzene, xylene, tetrachloroethylene, and many others (230) are consistently greater indoors than outdoors, even in smog-polluted areas, by factors of 2 to 5 and often by factors of 10 or more (79). Pesticide levels indoors are commonly greater by factors of 100 compared to outdoor levels (78,79). In food, residues from many common pesticides and herbicides, as well as direct chemical additives, are eaten in the average diet (231). Many of these substances are untested or inadequately tested (232), whereas many others are already known to be toxic (231,232). As illustration, Table 2 is an excerpt showing 8 from a list of 42 commonly encountered chemicals, where they are found, and their known toxic effects. The eight chemicals shown do not appear significantly different from the unshown entries in either number of sources or overall toxicity.
Table 2.
People who are middle-aged today were the first generation to have encountered these chemicals on a daily basis since birth. Because so few of these chemicals have had long-term testing, in a sense this generation is an experimental group. MCS is characterized by reactions to these chemicals, so it may be that MCS is the experimental result.
Initial Damage and Extensions. Model 2A will explore the possibility that specific configurations of increased multiple chemical exposure and stress can produce MCS through IDS interactions even though the IDSs are unchanged. In addition, Miller (90) and others (22,94) have developed models of MCS that propose sequential stages for MCS; common among these are susceptibility, sensitization, triggering, and spreading. For comparison's sake this description will adopt these stages; differences suggested by the IDS model will be discussed in "How Long is an Event?" Model 2A is shown graphically in Figure 4.
SUSCEPTIBILITY. As an example, suppose that a chronic low-level exposure (years long) to formaldehyde has created haptens and an IRA reaction in the subject (180-182). Assume that combined chronic chemical stressors such as SO2, NO2, and diesel exhaust particles are polluting the subject's work area simultaneously and also occurring in the subject's ambient urban air. These substances have impinged on the lung tissue (229) and a tolerance mechanism supplying compensatory lung tissue changes is occurring (20,48). Tolerance symptoms may not be noticed by the subject as a pattern because tolerance mechanisms are well known for moderating the magnitude of the reaction; in a sense, that is their function.
SENSITIZATION. A strong psychological anxiety (stress) occurs in combination with a moderately increased amount of formaldehyde. The anxiety induces the SR IDS. Because of the immune response already occurring and even increased slightly because of the increased level of formaldehyde, the crossover messengers between the SR and the immune response (for example, ACTH, -endorphins, IL-1 and -2, and immune cells, all of which are also involved in TDS) condition TDS to both formaldehyde and anxiety as inciters. Such bidirectional fertilization between psychological and chemical triggers is reported for TDS in animal experiments (3).
TRIGGERING. After some time the subject encounters a new chemical, benzene, while in a state of anxiety less severe than at the onset of the original event, so the SR IDS is not at first invoked. However TDS increases over time, even without exposures to the inciter; it is triggered by the anxiety. The tolerance mechanism, meanwhile, undisturbed during the sensitization stage, has continued to erode toward the exhaustion state (48). The added weight of the neurochemical and endocrine changes that characterize the TDS reaction causes the lung tolerance to air pollution to be breached and the NIR is invoked to deal with cellular damage that had been tolerated to that point. Under the influence of the concurrent benzene exposure, the APR is also cascaded from the NIR, and under the added influence of the TDS firing, the SR cascades. (Figure 4 shows a graphic separation of these events.) At this level of arousal TDS becomes conditioned to benzene also as a trigger, and we speculate that multiple overlaps in messengers between the TDS and the SR (Table 1) make it possible that the threshold for the SR becomes chained to the TDS response; in other words, the SR will be invoked directly by the TDS in future exposures.
1. Chronic formaldehyde induces the immune response to antigen. Simultaneously, chronic SO2, NO2, and diesel and other particulate matter from air at the workplace and urban home impinge lung tissue and induce tolerance in the form of compensatory lung cell architecture.
2a. Acute anxiety occurs in combination with moderately increased formaldehyde. The anxiety induces the SR.
2b. Crossover messengers interact between the SR and the IRA such as ACTH, -endorphins, IL-1 and IL-2, and immune cells.
2c. These messengers are also involved in TDS and TDS is invoked and conditioned to recognize both formaldehyde and anxiety as inciters.
3a. Later, subject encounters benzene during moderate anxiety. TDS has increased over time and is triggered by the anxiety.
3b. TDS reaction causes the already eroding lung tolerance to be breached and with continuing air pollution, the NIR is invoked to deal with cellular damage.
3c. Concurrent irritation/damage from the benzene exposure causes the APR to cascade from the NIR.
3d. Under the added influence of the TDS, the SR cascades.
3e. Multiple messenger overlaps chain the threshold for the SR to the TDS response so the SR will be invoked directly by the TDS in future. TDS also becomes conditioned to benzene as a trigger.
4a. Later, during moderate anger, benzene is again encountered along with alkylphenol novolac resin used in no-carbon forms. Benzene invokes TDS.
4b. TDS cascades the SR.
4c. Hormonal overlaps between the SR and anger increase anger's intensity.
4d. Messenger overlaps between increased anger, SR, and TDS cause TDS to become sensitized to alkylphenol novolac resin and anger as inciters.
4e. (Not shown.) In subsequent events this same spreading mechanism continues to add new stimulus chemicals and psychological stresses as TDS inciters.

Figure 4. IDS interaction model 2A, of MCS resulting from chemical and stress overload, adapted from the necessary stages of MCS suggested by Miller (90) and others (22,94).

SPREADING. In a later event benzene is again encountered along with a new chemical, alkylphenol novolac resin, which is used in no-carbon-required forms (242) and a new psychological stress, moderate anger. Now benzene causes TDS and hence the SR to fire, and the anger increases in intensity. The TDS becomes conditioned to both the new chemical, alkylphenol novolac resin, and to anger, the new stress, as inciters.
In subsequent events this same spreading mechanism could continue to add new stimulus chemicals and psychological stresses and new symptoms at diverse sites.
Notes on the Model. In Figure 4, tolerance, which is no longer active, is not shown in stage three; nor is the IRA; in our example formaldehyde is no longer being encountered. Additional possibilities that could have been included are that the IRA could develop an associated specific reaction to benzene or its metabolites or that the formaldehyde chronic exposure could continue.
Interactions from Other Models. In particular, pesticide and other chemical body burdens under model 1A and interactions between benzene and IL-1, model 1B, may be of interest in this model. Childhood window exposures (model 1B) and TD (model 1A) could also be added. The multiple-feedback autoimmunity to IgG model (model 1C) could also be used, say, by substituting vinyl chloride for formaldehyde as the chronic exposure agent, but at this point the complications become mind-numbing.
How Long is an Event?
Comparison of IDS Models with the Four-stage Model of MCS
Although the second exposure event in model 2A has been called triggering (stage 3) to match with the models of Miller (90) and others, several discrete sequential interactions are occurring within it, and this difference may be important. The time frame for several IDS interactions may be very short; a few minutes in high-stress situations. In testing it may be necessary to break down the IDS crossovers into shorter events to measure biomarkers meaningfully; otherwise the data will be chaotic. Figure 5 shows a superimposition of the IDS chaining during a single event, the stage-3 triggering of model 2A. Not only is the order of the chaining not easy to understand when lumped together, but any measurement of the crossed-over messengers such as ACTH, -endorphin, IL-1, etc. will appear random or otherwise incomprehensible if the measurements are taken at different times in the triggering sequence.

Figure 5. Possible source of MCS biomarker data error. This graphic shows combined IDS overlap events in the level 3 triggering stage of chemical and stress overload MCS model 2A. If biochemical markers are taken indiscriminately within this period chaotic data may result, since the same neuroendocrine-immune messengers may be in use for different purposes at different times. (Figure 4 shows separated event sequence.)

Another difference is that in the current IDS model (model 2A) both sensitization and spreading are also occurring during this triggering sequence, since a new IDS is being added to the mechanism (SR) and a new inciter is being conditioned (benzene). During the nominal spreading stage, triggering of TDS and stress are also occurring. It appears that through the architecture of the IDS interaction and chaining models, which are composed of short discrete events of several types, various sequences and combinations of triggering, spreading, and sensitizing can be obtained.
These differences between the IDS model and the four-stage MCS model have testing implications that are discussed in "Relevance of the Models to Current MCS Research Recommendations."
IDS Overlap MCS Model 2B: Allergic Mercury Reaction in Genetic Subset
Introduction. Human allergy to Hg has been recognized for a long time and although the specific genetic code is not worked out, this allergy is strongly suspected to be of genetic origin. It is estimated to affect between 2 and 5% of the human population (247,248). The North American contact hypersensitivity to Hg is reportedly 5.4% (249). Predisposition to mercury allergy has recently been investigated in genetically selected rodents. Interestingly, special rodent strains develop significant immune aberrations and autoimmune disease in Hg exposure, including exposure by implanted dental amalgam Hg configured as in human exposure (250,251).
In humans carrying dental amalgams, the amounts of Hg released have been estimated within the range that would cause reactions in those genetically susceptible to Hg (251). Therefore the millions of humans who carry Hg amalgams are theoretically at risk for genetically induced reactions. (Whether those not genetically susceptible could also be directly toxically affected by mercury is unknown; many widely divergent opinions and research reports have been published over the last few decades (247,248,251-256). Recent reports connect amalgams with oral cavity ill-health (248,257), increase in antibiotic-resistant bacteria in oral and intestinal cavities (258), multiple sclerosis (259,260), psychological complaints such as depression, excessive anger, and anxiety (261), and cardiovascular symptoms such as fatigue and high blood pressure (262).
Mercury is also available in the diet, particularly from fish. Levels of methyl mercury (MeHg) in fish appear to be growing and are a concern (263,264). An epidemiologic investigation of a fish-eating population is reported to show high susceptibility to brain damage during prenatal exposures to MeHg (263). Also Hg in paint is a widely recognized health hazard (265-267), as is skin-lightening cream (268). A syndrome of infant Hg toxicity called acrodynia is reported from application of calomel teething powders (255) and from paint exposures (267). A case-control study shows increased urinary Hg in people living in houses painted with Hg-latex paint (p<0.001) (267), and a case of acrodynia occurred in a child living in such a house (267). Before 1990 one-third of the interior latex paint used in the United States had added Hg fungicide (267).
Like MeHg, Hg is toxic to the CNS and established detrimental effects range from behavioral irritability and insomnia at low levels of exposure through tremors, muscle spasms, and nerve conduction loss at higher exposure levels (253). Many other toxic effects are reported (255), including cardiovascular (262), immune (248,255), and autoimmune effects (269).
Data on a direct connection of Hg exposure to MCS is lacking except for the synchronicity of neurologic symptoms, which are the most highly reported symptom category in MCS clinical literature and the symptoms most commonly produced by Hg. These reasons and the demographics prompted this exploratory model. Half the population of the western world has Hg amalgam fillings, and 5% may be allergic to Hg.
Initial Damage. We hypothesize a human strain that has a genetically determined immune response to Hg and a subject who has sufficient dental Hg released in the body to induce a systemic autoimmune reaction through the IRA. Subsequent to this the Hg level in the subject's body is being increased by food sources, further increasing the activity of the autoimmune response. Then a moderate-to-high exposure to toxic environmental Hg in paint, drugs, pesticides, cosmetics, or other source occurs during a stressful situation that includes a chemical exposure. For example Hg in fresh paint, in cosmetics or calomel, or in amalgam implantation in a dentist's office in conjunction with anesthetic injection or ambient chemicals might provide this combination. This exposure causes SR activation, and in combination with the ongoing autoimmunity, a combined CNS-mediated TDS to Hg and to the stress-associated chemical may begin. Because there is already an appreciable body burden of Hg and also an immune response to this Hg, there may be a messenger crossover--ACTH, -endorphin, IL-1, or other immune cells or messengers, for example--between the TDS and the immune and SRs. This may change the threshold of response of any of these IDSs. This combined sensitization of the immune response and TDS to internal Hg may create an unstable situation that allows subsequent exposures to become conditioned inciters of the TDS during various situations; e.g., those that elicit movement or increase of the Hg body burden while stressing psychologically or chemically.
Extensions. HEAVYMETALS/ZINCDISPLACEMENT. Cd, Pb, and Hg are all Zn agonists, and rising levels of Cd and Pb can add to the toxic effect of Hg in the body. Metals are unique in the environment in that they are not consumed by human enterprise and so continue to increase in the biosphere as we collect and process them (270); one review concludes that we have a growing problem of heavy metal toxicity (270). Cd is increasing in human tissue. It has a human half-life of 30 years (271) and the average human body burden since the turn of the century has increased by a factor of 4.7 according to one study (272), with the renal concentration increasing by a factor of 47 (272). Another study found a renal increase factor of 3.8 (273). Cd is a potent developmental toxin in animal studies; its effects include CNS and behavioral dysfunctions and many others (274). Some Cd effects have been linked to its displacement of Zn from various enzymes (270,274), and Cd from maternal smoking is thought to decrease the transfer of Zn across the human placenta (275,276), which may implicate Cd in multiple teratogenic effects strongly suspected to result from Zn gestational deficiency (44,193). Pb caused a reduction in cognitive development through 7 years of age in children living in a lead-smelting community (277). Pb is also reported to cause DNA-protein crosslinks and DNA repair inhibition (270), and to accumulate in the hippocampus of children, rats, and monkeys. In monkeys the effects are accompanied by Zn displacement and learning deficits (278).
CHILDHOOD ORGESTATIONALMERCURYEXPOSURES. MeHg exposure during pregnancy causes neurologic abnormalities, including psychomotor deficits, mental retardation, and deafness in children (279). Fetal effects occur at much lower exposure levels than required for effects in adults, although in both cases effects are almost exclusively on the nervous system, especially the CNS (268). Hg is not known to damage the fetus as heavily as MeHg, but this may be because of lack of study (253).
Combining Extensions to Produce Variants of MCS. Body burdens of chemicals, preexisting TD, early and ongoing Zn deficiency described under model 1A, and childhood window exposures and hapten spreading described under models 1B and 1C could also interact in this model. Again various subsets of the MCS syndrome might be produced depending on which of these substrates is present.
Concluding Note on Inadequate or Inappropriate IDS Models 2A and 2B. In these two thought experiments, physiologically healthy MCS subjects appear plausible through various interactions of the nine IDSs. That is, it may be that in some forms of MCS the subjects' neuroimmune-endocrine systems are functioning well--within the limits of their present design. These design limitations may now be coming to our attention because of interactions with increasing concentrations of new types of toxic chemicals and metals and possibly new levels of stress. In this model those who have MCS are at the end of a normal distribution; i.e., they have been unlucky in how many chemicals and how much stress and heavy metal they were exposed to or in what synergistic combinations. They may have marginally different thresholds to TDS, kindling, or other IDSs than the norm. A disturbing correlate of these models is that an increasing population in the industrial world may be at risk for developing MCS.
Model 3: IDS Overlap MCS as Evolution and Learning
As discussed earlier, the immune system most likely predates the CNS. The immune system has evolved specifically as a learning mechanism. It has the function of mapping its biochemical environment i.e., to recognize and remember biochemical danger patterns (10). Partly to achieve this purpose, it is closely linked to the CNS (1,10,29-34,42,158,280-284) and the endocrine system (10,29-31,34,158,281). Grossman et al. (10) propose that each cell is a complex feedback-controlled unit and that different cells learn to respond preferentially to different combinations of signals in their immediate biochemical environment. These signals may originate from the CNS or externally. In addition, the recent T-cell receptor recombination discoveries that make genetic encoding of specific antigens more possible (26,201,202) lead to the possibility that changes in the thresholds of various of the IDSs will be encoded genetically either within the present generation or in future generations or both. At least four different means of varying the DNA recombination code for T-cell receptors have been identified (26), and some method of saving the known toxic compounds into the germline might be an evolutionary advantage. Recent work by various researchers has pointed to adaptive genetic learning as a major possibility (201,202). In bacterial studies genetic mechanisms are reported that accelerate and direct DNA mutation during stressful situations (201).
It appears that the neuroendocrine-immune system is purposely unique in each individual, and part of this comes from experience. Jerne (7) suggests that "Early imprints leave the deepest traces."
If we consider the crossover messengers (Table 1) used by most IDS--messengers such as IL-1, ACTH, and -endorphin, MT, mast cells, etc.--limited resources the body allocates between IDS in times of attack, we may, in a semantic reorientation, be able to model IDS threshold changes as a learning effect rather than inadequacy or damage. It would be reasonable also if the body set these allocation ranges in advance; that may be one function of childhood windows and of neuroimmune learning in general. For instance TD can produce MPD alternative personalities that have differing immune responses (65) and many other lifelong physiologic differences; the appropriate alternative personality appears in a specific context then disappears when the context changes. Various combinations of IDSs therefore may be interacting meaningfully to adjust thresholds in readiness for special situations.
Childhood developmental windows could be understood then not only as times when toxicants can accidentally produce more damage but also as specific times when the IDSs are sampling the external environment to determine a range of response appropriate for the lifetime of a particular individual.
In a species sense MCS may conceivably constitute a healthy response to an unhealthy environment. Although MCS symptoms frequently are painful, pain can have a useful function. That is, since the chemicals MCS individuals avoid are known to be toxic in high concentrations and are also increasingly recognized as toxic and carcinogenic in chronic exposures (239,285), (Table 2), such a difference could be viewed as an improvement in the species. People who get MCS would be subject to lower rates of chemical damage and cancer because they would have an increased impetus to avoid the toxicants.
In such a model we consider it possible that it is through such IDS learning mechanisms that people with MCS have learned to abandon almost all aspects of 20th-century life that involve the smell, touch, and taste of rubbers and synthetic foams, new plastics, fresh paints, petrochemical cleaners, oil and gas fuels, and petroleum-based pesticides, perfumes, food additives, and drugs; also that their inability to be near these chemicals is probably lifelong (89). We may even imagine that persons with MCS may find themselves living in an electrically heated rugless house in a small village far from a city, with a yard bordering a wild field. When they sit in the yard on a sunny day breathing good air, listening to the birds chirping, watching their organic garden growing, and looking at the car parked in the driveway, which they can only use once a week for a 20-min trip, it may occur to them that their MCS disease--as a learning experience--might not be such a bad thing in some ways.
Testing the IDS Overlap Models
Relevance of IDS Models to Early MCS Research. One research team investigating MCS combined masking odors such as peppermint, cinnamon, and anise with a challenge chemical so that the patient could not identify the odor of the chemical being administered (286). The author of at least one paper on MCS (287) has called for similar odor-masking studies. However odor, taste, sound, and sight--CNS perceptions--can function as conditioned stimuli (11,13). Accordingly, if MCS is a complex conditioned phenomenon, removing these stimuli may result in studies that do not find a reaction in at least some MCS patients. For instance, according to the models developed in this paper, odor may be linked in the patient's memory with acute unpleasant experiences, and by an associated IDS linkage (such as TD) may cause multiple reciprocal CNS-immune messengers [IL-1 (159,288,289), IL-6 and IL-8 (290), substance P (1,283), somatostatin (32), and VIP (33), for example] to cascade and perhaps lead to the SR (8,30,280,281,288). If such odor response is blinded, such studies could erroneously conclude that MCS did not exist.
Relevance of the IDS Models to Current MCS Research Recommendations. If biomarker data are pursued and the interactive models developed in this paper are even partially on the right track, complex nonlinear biomarker data will be required. But how do we even know who has MCS? It has been calculated that if only 10% of a study population are responders, then to achieve a response shift of one standard deviation from norm, with p=0.01 90% of the time, the study population would need to be 2102 people, but only 23 people if 100% are responders (291). Thus, defining a small population of people with MCS in the absence of reliable biomarkers is a catch-22. Perhaps long-term self-control crossover studies (291,292) that can measure data at various points in the triggering-spreading sequence would be more useful, but the number of such studies that could be economically carried out in a limited timeframe is small. Also there is no way to know if we are measuring people with MCS or people who are willing to spend time in a physician's office.
Recent research groups working on MCS testing (84,293) recommend using only people who have had a verifiable single-exposure event precipitating their MCS. But how representative of the entire population is this? Not only do we not know how many gradual onset cases are being left out, the crossover with chronic fatigue and fibromyalgia, among other conditions, is reportedly high. These conditions may even be indistinguishable in most cases (89). If it turns out that an IDS model accounting for all these effects simultaneously is required--perhaps what Miller has called "an emerging category of disease" (294)--then limiting studies to only a small number of adult single-event precipitated MCS cases in a clinical setting may seriously decrease our knowledge base for building the pattern.
An additional serious problem with clinical testing discussed in "Working Definition" is that some of the IDS models developed in this paper predict that people with MCS will have psychological reactions in a testing situation, which will distort results. Conversely they may require a particular type of psychological stress to produce their reaction, and such stress may only occur when they are in their ordinary life settings. Bell et al. (86), in their working-group report on MCS testing, referred to the need to avoid novelty in testing situations (a variant of this same problem) and concluded, "it will be essential to perform multiple, not one exposure sessions separated in time....That is, it is necessary to initiate and elicit sensitization within the same experiment." This is an important limitation and may be difficult to achieve. Cohen et al. (293), in another working group, state the problem clearly: "Do events perceived as stressful in the recent or past history of the individual play roles in the onset and/or progression of MCS? ...Which factor is more important in the traumatic initiation: the exposure to chemicals associated with the traumatic event, and/or the stressful experience associated with the event? Can a stressor precipitate MCS in a chemically sensitized individual who is not displaying overt symptoms of MCS at the time of stressor exposure?"
Yet their recommendations on the design of controlled exposure studies (293), according to my interpretation, do not circumvent this. In making recommendations on testing three other working groups from the same conference (77,84,295) made no reference to this problem, yet it seems crucial.
Animal studies may help clarify the situation. The Bell et al. (86) working group suggests a series of experiments on rodents with each series taking measurements from microelectrode bundles in the brain. The series roughly measures: a) chemical odor only, b) stress first, then chemical odor, and c) chemical odor first, then stress. This allows the use of stress, which the human model does not. It does, however, leave out variables explored in some of the IDS models; for example, it has no simultaneous stresses and chemicals and no provision for combinations of early developmental windows, body burdens of chemicals and metals, gestational and chronic Zn deficiency, or a genetic allergy. These variables could be added in future experiments, but finding the right combination(s) might be time consuming and possibly even prohibitive in nonhuman subjects.
Also there is the problem outlined in "How Long is an Event? Comparisons of IDS Models with the Four-stage Model of MCS" that several very short IDS-chaining events may be being lumped together under what is nominally called sensitization, triggering, or spreading. Additionally, these events may constitute combinations of sensitization, triggering, and spreading and even more importantly may use identical messengers that perform changing functions within very short time spans. Unless the measuring protocol is programmed for such shifts, chaotic biomarker data could result.

Re: CFS, MCS, LGS, & SR. WOW !

Posted by Part 4 on March 15, 1999 at 21:33:13:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by Part 3 on March 15, 1999 at 21:26:03:

Also there is the problem outlined in "How Long is an Event? Comparisons of IDS Models with the Four-stage Model of MCS" that several very short IDS-chaining events may be being lumped together under what is nominally called sensitization, triggering, or spreading. Additionally, these events may constitute combinations of sensitization, triggering, and spreading and even more importantly may use identical messengers that perform changing functions within very short time spans. Unless the measuring protocol is programmed for such shifts, chaotic biomarker data could result.
Rigorous double-blind (84) and balanced-placebo design (295) clinical testing suggested by some work groups may be critical in convincing other investigators, doctors, and legislators of the legitimacy of MCS as a debilitating condition, and should probably be undertaken immediately. But these tests may not identify the origins of MCS. An analogy is that for a century it has been possible to view the symptoms of MPD or BPD in clinical settings and the disorders have long been accepted as valid. Yet only recently has a convincing etiology been discovered (57,58,60,65,66); this has been through collating large numbers of patient questionnaire self-reports. These early traumas were not available in clinical settings to either the people who experienced them or the health care workers who had not.
Identifying MCS Mechanisms by Large-scale Self-report Epidemiology. An alternative investigation route that appears logical is large-scale self-report epidemiology of MCS. After decades of argumentative discourse among the medical profession and the press, people with MCS are aware and beginning to get organized, even if they do not congregate in cities or at conferences. They act most frequently through newsletters and memberships in local self-help organizations. There are many national organizations and newsletters, especially when the associated conditions of fibromyalgia and chronic fatigue are considered. It is possible that by using e-mail and the telephone, 10 organizations could quickly be found that would each provide addresses for 500 persons. Within a short time, a mailing could be sent to 5000 people, all of whom had self-defined long-term MCS. This mailing could be done either at the same time as or in advance of animal and clinical studies called for by the research groups working on MCS.
One suggestion might be for each member of a panel of six to eight people who have been studying this condition for many years to produce 50 to 100 questions based on his or her work. These questions would then be collected, sorted, and culled to a workable number--perhaps 150 questions. These questions would be mailed, returned, and statistically analyzed for useful patterns that might suggest directions for future testing and research.
It appears appropriate to suggest that at least one panel member prepare questions based on the IDS interaction models. It also seems reasonable to have at least one panel member with overt MCS symptoms and who has lived with MCS for an appreciable period of time. This might expand the functional perspective of the panel; and help validate the undertaking for those approached to contribute addresses and contacts as well as those asked to complete the questionnaire. It would also be important that at least one panel member have previous experience with wide-area questionnaire preparation, distribution, and analysis. Finally, including some carefully designed open-ended and single- and multiple-choice types of questions might allow more robust cross-checking of the data. This has recently been demonstrated in a long-term questionnaire study searching for developmental correlates in an adult population (296).
Available evidence is consistent with a category of disease that develops through the interaction of existing human IDSs. Three models of such IDS disease generation are suggested: damaged IDSs, inappropriate or inadequate IDSs, and evolving or learning IDSs.
Several nonexclusive mechanisms of MCS based on these IDS models appear plausible. If one or more of them are accurate, demonstrating the existence of MCS and verifying its mechanisms may involve a simultaneous study of clinical, animal, and large-scale self-report data.
Additional Descriptions of IDSs: Mode of Action and Inciters
Definitions and range of physical response for each IDS are discussed in "Integrated Defense System Overlaps as a Disease Model." Table 1 lists the IDS models with range of physical action and inciters.
Time-dependent Sensitization
Mode of Action
In animals, when one or more noxious chemicals or stresses are encountered above a certain threshold level through any body exposure route, responses related to survival (297) occur in the CNS, endocrine, and immune systems. Later when this same stressor is encountered, this response has increased (sensitization) or other stressors or chemicals are now sensitized (spreading). Intermittent stress encounters prolong or increase sensitization; continuous ones may induce tolerance (3,22). TDS sequelae in humans have been suggested to include paranoid schizophrenia, panic disorder, PTSD, and MCS. Associated neurologic changes appear to be irreversible. TDS has been postulated to be "...dependent on changes or alterations in gene expression" (298). Behavioral and neurochemical responses of genetically different rats showed significant differences in the development of TDS (297); hence, human host susceptibility to TDS may differ appreciably with different inciters or mediators.
There are many chemical and nonchemical stressors. Chemicals include: amitriptyline, amphetamine, haloperidol, ethanol, IL-2, nicotine, and corticosterone. Nonchemical stresses include immobilization, shock, syringe insertion and withdrawal, saline injection, and time in a strange environment (3).
Immune Response to Antigen
Mode of Action
Description of the antigen-specific immune response to follow is highly simplified, partly because of the "virtual explosion of information that has taken place within the field of immunology" (2) in recent years and partly because the immune system is so closely complexed with the central nervous and endocrine systems.
In brief the specific immune response has the important characteristics of long-term memory through memory cells and probably genetic coding; tolerance through suppressor T cells that modulate other immune functions; and associative spreading of the response by recognition of multiple epitopes on one antigen, and possibly by other mechanisms such as CNS-mediated conditioned learning.
T lymphocytes are activated by antigen presented to them by macrophages or other presenter cells, and in turn they grow, multiply clonally, and begin expressing molecular messengers that in turn activate B cells, other T cells, and other types of cells to aid in attack and other responses to that specific antigen (2). Many of these messengers communicate directly with receptors in the endocrine organs or on CNS cells (32), so the response can involve all body systems even if the antigen is local. The immune responses can in turn be modified by input from the CNS and endocrine messengers. In addition an autoimmune T-cell-mediated response is sometimes mounted against the host's own tissue. This can occur when the tissue is complexed with a foreign antigen or for other unknown reasons.
A major discovery of recent years is that antigen-specific memory T cells, which will precipitate a faster, stronger response on second encounter with the antigen than naive T cells (203) and B cells, can sometimes persist for a lifetime (203) without any intervening booster encounters with the original antigen (5,299).
Another important recent discovery is that the antigen-recognizing T-cell receptors undergo directed gene rearrangement early in T-cell growth in the thymus (26,28). Thus, it appears possible that antigen recognition is being genetically encoded (201,202), although such a feedback loop has not been characterized in detail.
Inciters include bacteria, fungi, and viruses, other foreign tissues, self-tissues in autoimmune reactions, chemicals such as phenol, alcohol, formaldehyde, toluene diisocyanate, PCBs, and polybrominated biphenyls, metals such as Hg and nickel, and messengers from the nervous and endocrine systems including those induced by psychologic or physical stresses.
Mode of Action
Kindling was the name given the effect observed when brief applications of same-strength electricity to the brains of animals produced stronger and stronger reactions--from no reaction through electroencephalogram changes to full convulsions even after stimulation had stopped (4). Partial kindling produces behavioral changes secondary to brain chemistry changes, and in humans chemical partial kindling has been used to explain lasting panic disorder and anxiety (22). Behavioral changes secondary to kindling have been postulated to result from the major part the limbic system plays in controlling survival activities.
Various chemicals evoke a kindling response in humans (22). These include cocaine, amphetamine, -endorphin, lidocaine, physotigmine, and the pesticides lindane and dieldrin. After initiation physical stressors and morphine have been noted to be inciters (22).
Nonspecific Immune Response
Mode of Action
The so-called innate (39,161) immune system can be viewed as any first-line immune reaction to an unanticipated pathogen. The first contacts include mast cells, NK cells, collectins such as MBP, macrophages, T cells, and B cells. After contact with pathogenic bacteria, fungi, viruses, lectins, or superantigens (162) or after stimulation by neuropeptides such as substance P (1), various mediators are expressed to produce cascading reactions, including proliferation of the original cells. For instance, mast cells produce TNF-, IL-1, IL-3, IL-4, IL-6, GM-CSF (40), and histamine (1), which have multiple effects on T, B, and other immune cells and on receptors in the nervous and endocrine systems, whereas MBP induces complement-mediated responses such as killing of bacteria (39).
NIRs are elicited by such factors as microorganisms (bacteria, fungi, viruses); lectins from a wide range of plants, animals and fungi, some of which are common in the diet (peanut, wheat germ, potato, tomato, various legumes, and others); exogenous superantigens such as staphylococcal enterotoxins (162); endogenous superantigens (162); chemicals such as phenol resins (242) and dimethyl sulfoxide (300); and neuropeptides such as somatostatin, substance P, and VIP (32). Stress suppresses nonspecific T-cell proliferation (14).
Acute-phase Response
Mode of Action
Tissue damage or infection (as opposed to a psychological stress; see "Stress Response") causes principally macrophages, platelets, and blood monocytes but also mast and other cells to release cytokines such as IL-1 and TNF, which have both local and distant effects (41,289).
Locally a second wave of cytokines is released by stromal cells, and local endothelial cells undergo changes that induce leukocytes into the tissue. An arachidonic acid cascade occurs, including prostaglandins and thromboxanes, and vascular tone changes occur, swelling and redness, for example. Histamine, serotonin, and platelet-activating factor change tissue flow of fluids. Pain occurs through molecules such as bradykinin, which are released during clotting (41).
Distantly the interleukins and TNF can have multiple effects (29,158,288), including changing the hypothalamic temperature setting (fever) and inducing changes in liver metabolism. Distinct sets of acute-phase proteins are induced separately in the liver by IL-1 as opposed to IL-6-type cytokines (41); the former include glycoprotein, C-reactive protein and complement C3, the latter include fibrinogen and antiproteases (41,288). Liver changes also include production of MT and the consequent lowering of plasma Zn levels (44,138,301).
These cytokines can also induce ACTH from the adrenal-pituitary axis, generating corticosteroids that feed back to suppress the immune reactions (6,41); this can be accompanied by direct production of analgesic -endorphins by B cells (31). At this point the CNS is directly involved, as CRH can be induced in the brain by interleukins and psychological stress (281), and it induces ACTH and hence corticosteroids. This description merges with that of the SR described below.
Although it may be that the APR diminishes by an undirected erosion over a 24- to 48-hr period, it is also reported that IL-4 and IL-10, produced by some T cells, can accomplish downregulation of IL-1, IL-6, and IL-8 (41).
Physical tissue injury and infection by microorganisms are described as primary inciting mechanisms (41). Based on Zn/MT fetal damage studies, induction may also occur through contact with toxic environmental chemicals such as urethane, ethanol, and others (44,192).
Stress Response
Mode of Action
Coordinated responses take place when a systemic threat is perceived. This perception may be triggered through release of immune mediators such as IL-1, IL-2, IL-3, IL-6, TNF, and prostaglandins (6,281) resulting from a local injury, trauma, or infection or it may be induced centrally first, by psychological stress (281,302) for example.
With central perception of stress, several feedback loops are invoked within the neuroendocrine-immune system; the interactions between these, although complex, presumably determine how the response occurs, its intensity, and how long it lasts (31,281).
The main functional changes are energy redistribution toward improved attention and alertness and suppression of less essential behavior such as feeding and sexual interest (6). The brain, certain muscles, and other organs of immediate need are supplied with more oxygen and nutrients (6).
The immune response is also significantly suppressed at various levels (6). This has been well documented (29,32,281,303) and includes cells (macrophage, T, B, NK, etc.) and downregulation of cytokines such as IL-1, IL-2, and others (304-306). Less research reports differential effects, with some immune parameters showing increased activity (303); this may be time dependent (305).
The main effectors are corticosteroids and catecholamines; the former have been more extensively documented and are presumed to be centrally induced, although this may prove not to be true with the advent of newer evidence. CRH, induced in the brain by stressors (including interleukins) induces ACTH from the pituitary and thus corticotropin from the adrenal gland. CRH is associated with SR behaviors such as anorexia, decreased libido, and motor activity changes. Fear responses and decrease in willingness to explore have been reported at higher dosages (6).
CRH also induces--and is induced by--the central autonomic arousal system (norepinephrine), resulting in simultaneous expression of catecholamines, which contribute, with the glucocorticoids, to both behavioral and immune effects.
SRs may be elicited by immune-mediated infection, physical trauma, the APR, psychological trauma, drugs (297), environmental chemicals, muscular exercise, cold (48), solar radiation (48), and natural and synthetic estrogens (48).
Neurogenic Switching
Mode of Action
A recently named hypothesis by Meggs (46,307,308) explains how antigen, stress, chemical exposure, or damage at one body site might lead to diverse symptoms at multiple distant sites. Anaphylactic reactions and food-allergy symptoms are some suggested end products.
On the one hand mediators such as IL-1 and IL-2 participating in IgE and other immune responses also affect the release of neuropeptides such as substance P from nearby nerve cells. On the other hand, substance P, a known participant in neurogenic inflammation caused by chemicals, also can incite the IgE response and cause other immune changes. Thus a feedback loop can be initiated.
Although not using the term NS, another review (32) has shown how this could happen in the intestines, where neuropeptides substance P, somatostatin, and VIP are produced by nerve cells, received by various immune cells, and produced by various immune cells.
Because we know the CNS can be conditioned to control immune responses (10), for instance to have an audiovisual signal control IgE response to egg albumin in the intestines (13), and that immune responses can quickly become systemic reactions that include CNS modulation (such as in anaphylactic shock after insect bite), this feedback loop of cross-communication between adjacent nerve and immune cells has been suggested to be a likely candidate for explaining such puzzling conditions as migraine, asthma, arthritis, and MCS (46).
Almost any exogenous or endogenous agent recognized by the immune or peripheral nervous system or by higher CNS processing centers may be involved. This includes such factors as stress, chemicals, foods, organisms, and self-proteins.
Mode of Action
Tolerance corresponds to stage 2 (resistance) in Selye's well-known three-stage general adaptation syndrome model for response to chronic stressors (48). Stage 1 is alarm reaction, which corresponds to a combination of the APS and SR described above and stage 3 is exhaustion where the organism has lost its ability to defend by adapting and unregulated damage is occurring.
Because an overall mechanism for the induction of tolerance has yet to be postulated, we remain at the descriptive stage. However tolerance is so widely reported in human and other life-form responses to various insults that it may be useful to define it as being any back-up system developed by an organism that allows it to more successfully bear a chronic injury.
Tolerance eventually gives out. In other words all of the forms of tolerance described below--with the possible exception of certain forms of nonpathogenic food tolerance (49)--delay or minimize damage but eventually succumb to a long-term chronic stressor. During this process of succumbing (exhaustion) (48) systemic changes occur; e.g., rat lungs may lose tolerance to NO2. Stephens et al. (20) describe this process as follows "...pathogenesis continued to produce additional alterations at various biological levels, first stepwise and then simultaneously, and so become identified at some point as a 'clinical entity'...It appears that adaptation may not be sustained in the face of persistent stimulation from an injurious agent...."
Reported examples of tolerance include changes in Escherichia coli colony-forming when treated with Cd (309); in rat lung tissue repair in response to NO2 (20) and gasoline (310); in human psychophysiologic responses such as body balance and reaction time to inhaled xylene (311), ozone, and various solvents (53); and in response syndromes to Zn oxide fumes, nitroglycerin, and cotton and other grain dusts (47). One review of examples (47) imputed to tolerance and its interruption tells of: brain- and CNS-mediated behavioral effects; asthma; an infectionlike syndrome that includes fever, coughing, nausea, and weakness; a syndrome with drowsiness, severe headaches, and vomiting that sometimes includes violent behavior; a syndrome with airway irritation, coughing, pulmonary function test reductions and red blood cell fragility; emphysemalike changes and fibrosis; olfactory fatigue; and excess stimulation and tiredness in an alternating pattern (indicating repeated tolerance interruption).
A special type of tolerance has been proposed for the immune system; various cells such as T and B cells are widely believed to function by suppression (7,55) and anergy (54), which are forms of self-controlled tolerance. Yet another form, food tolerance or intolerance, also involves the immune system, including the immuo-globulins, but may be distinct since it has some unusual features (49). Addiction, including food addiction (312), has been described as an unfortunate type of tolerance (47,52); in this case, the organism procures and self-administers the insulting agent to enjoy certain aspects of the tolerance mechanism (52) or to ensure that tolerance continues (47,312).
Masking and masked addiction are terms applied to the inability of a self-conscious organism to know the inciting agent (78). It occurs during tolerance when the exposures are continuous and the symptoms are diffuse. It can occur for foods (312) and it has been proposed that masked tolerance to household chemicals is a significant unrecognized health problem (313).
At least one tolerance mechanism is described as proceeding by adaptive changes in DNA transcription (309). Possibly the recent change of scientific paradigm (still under debate) that allows for directed genetic adaptation (28,202) as opposed to merely random mutation will stimulate our understanding of other DNA mechanisms of tolerance if these exist.
Tolerance mechanisms have been suggested as an underappreciated reason why dose-response curves are frequently nonlinear (51).
Possibly any chronic stress can evoke tolerance responses. Examples reviewed (47,51,52) and reported to induce tolerance include diverse inhaled chemicals and particle dusts including cotton and grain dusts, ozone, xylene (311), NO2 (20), nitroglycerin, systemic lead and cadmium, welding fumes from Zn, copper, magnesium and aluminum, solvent fumes from paint, varnish, adhesives, pesticides, and cleaning solutions, caffeine, cigarette smoke, narcotics, cocaine, marijuana, alcohol, formaldehyde, gasoline (310), gas combustion products, and continuously consumed allergenic foods (312) such as corn, milk, eggs, wheat, beef, pork, and citrus fruit, and immune-defined antigens such as infectious microorganisms and dietary lectins (54).

Re: CFS, MCS, LGS, & SR. WOW !

Posted by References on March 15, 1999 at 21:37:21:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by Part 4 on March 15, 1999 at 21:33:13:

Traumatic Dissociation
TD is described in full in "Integrated Defense System Overlaps as a Disease Model" under "Traumatic Dissociation."
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Re: CFS, MCS, LGS, & SR. WOW !

Posted by References 3 on March 15, 1999 at 21:41:05:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by REFERENCES 2 on March 15, 1999 at 21:39:32:

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Re: CFS, MCS, LGS, & SR. WOW !

Posted by Profile - Ziem on March 15, 1999 at 21:46:35:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

Profile of Patients with Chemical Injury and Sensitivity
Grace Ziem1 and James McTamney2
1 Occupational and Environmental Medicine, Baltimore, Maryland
2 Clinical Psychologist, Lutherville, Maryland
Patients reporting sensitivity to multiple chemicals at levels usually tolerated by the healthy population were administered standardized questionnaires to evaluate their symptoms and the exposures that aggravated these symptoms. Many patients were referred for medical tests. It is thought that patients with chemical sensitivity have organ abnormalities involving the liver, nervous system (brain, including limbic, peripheral, autonomic), immune system, and porphyrin metabolism, probably reflecting chemical injury to these systems. Laboratory results are not consistent with a psychologic origin of chemical sensitivity. Substantial overlap between chemical sensitivity, fibromyalgia, and chronic fatigue syndrome exists: the latter two conditions often involve chemical sensitivity and may even be the same disorder. Other disorders commonly seen in chemical sensitivity patients include headache (often migraine), chronic fatigue, musculoskeletal aching, chronic respiratory inflammation (rhinitis, sinusitis, laryngitis, asthma), attention deficit, and hyperactivity (affected younger children). Less common disorders include tremor, seizures, and mitral valve prolapse. Patients with these overlapping disorders should be evaluated for chemical sensitivity and excluded from control groups in future research. Agents whose exposures are associated with symptoms and suspected of causing onset of chemical sensitivity with chronic illness include gasoline, kerosene, natural gas, pesticides (especially chlordane and chlorpyrifos), solvents, new carpet and other renovation materials, adhesives/glues, fiberglass, carbonless copy paper, fabric softener, formaldehyde and glutaraldehyde, carpet shampoos (lauryl sulfate) and other cleaning agents, isocyanates, combustion products (poorly vented gas heaters, overheated batteries), and medications (dinitrochlorobenzene for warts, intranasally packed neosynephrine, prolonged antibiotics, and general anesthesia with petrochemicals). Multiple mechanisms of chemical injury that magnify response to exposures in chemically sensitive patients can include neurogenic inflammation (respiratory, gastrointestinal, genitourinary), kindling and time-dependent sensitization (neurologic), impaired porphyrin metabolism (multiple organs), and immune activation. -- Environ Health Perspect 105(Suppl 2):417-436 (1997)
Key words: multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, neuropsychological tests, toxic encephalopathy, autoimmunity (or autoimmune diseases), immune activation, acquired disorders of porphyrin metabolism (or porphyria), chemically induced, pesticides, solvents, respiratory inflammation
This paper is based on a presentation at the Conference on Experimental Approaches to Chemical Sensitivity held 20-22 September 1995 in Princeton, New Jersey. Manuscript received at EHP 6 March 1996; manuscript accepted 26 November 1996.
The authors gratefully acknowledge the assistance of B. Cook with record retrieval, G. Smith and C. Prigg with typing and data entry, and A. Donnay with editing and designing tables and figures. Donnay also provided many invaluable suggestions and assistance with the content of the manuscript.
Address correspondence to Dr. G. Ziem, 1722 Linden Avenue, Baltimore MD 21217. Telephone: (410) 462-4085. alternate phone (410) 448-3319. Fax: (410) 462-1039.
Abbreviations used: AAL, Antibody Assay Laboratory; ALA-D, aminolevulenic acid dehydratase; CD, cluster of differentiation; CFS, chronic fatigue syndrome; conA, concanavalin A; CpgO, coproporhyrinogen oxidase;; EEGs, electroencephalograms; ISL, Immunosciences Laboratory; MCS, multiple chemical sensitivity; NK, natural killer cell; PbgD, porphobilinogen deaminase; PHA, phytohemagglutinin; SPECT, single photon emission computed tomography; WAIS-R, Wechsler adult intelligence scale-revised.
Introduction The study of medicine "begins with the patient, continues with the patient and ends ... with the patient," according to William Osler (1). Exposure to chemicals, particularly petrochemicals and combustion products, has been associated in the literature with a variety of alterations in bodily functions. Porphyrin disturbances of various types following chemical and heavy metal exposures were reported by several authors in a special conference on chemically induced porphyrinopathies sponsored by the New York Academy of Sciences (2). Abnormally elevated levels of urinary coproporphyrins were reported in several papers, but other fecal and urinary porphyrins could be increased as well. Specific types of heavy metal and petrochemical exposures seem to cause specific patterns of porphyrin disturbance in rats (3). Chlorinated benzenes can induce porphyria in rats (4), and small exposures (such as swallowed mouthwash) can aggravate congenital porphyria (5). Immune disturbances following chemical exposure have been reported by several authors. In the following immune references, patients were studied only after probable causal exposure and the results were compared to those of laboratory normals. Impaired mitogenesis has been noted after exposure to chlordane (6) and isocyanates (7). A higher number of helper cells have been described in workers exposed to solvents (8) and isocyanates (7), and in persons consuming chlorinated solvents in drinking water (9). A greater number of immune complexes are reported with vinyl chloride exposure, and scleroderma has been noted after aromatic or chlorinated solvent exposure (10). Immune activation with higher levels of TA1/CD26 has been reported with isocyanates (7), formaldehyde (11), formaldehyde with aliphatic amines (12), silicone (13), chlordane and chlorpyrifos (14), and sick-building exposures (15).
Higher levels of abnormalities in various autoantibodies are described after a wide variety of chemical exposures, including chlordane (6), solvents (16,17), chlorinated solvents (9), polychlorinated biphenyls and polybrominated biphenyls (18), organochlorine, organophosphate and other pesticides (19), formaldehyde and aliphatic amines (12), silicone (13,20), chlordane (14), chlorpyrifos (14), malathion (14), and formaldehyde (11). A greater number of chemical-specific antibodies has been noted after exposure to building materials in remodeling (21). Suppression of mitogenesis (22) and natural killer cell (NK) function (23) has been described following anesthesia induced by petrochemical agents. Reduced NK function in multiple chemical sensitivity (MCS) patients also has been reported by Heuser (24).
Neurologic effects long have been associated with exposure to petrochemicals. Solvent exposure is associated with autonomic dysfunction (25), neurocognitive impairment (26,27), vestibular abnormalities (28), and impaired hearing (29). In a study of the effects of solvents on 15 industrial painters (30), impairment was observed on a variety of neuropsychological measures. The Halstead-Reitan Battery was administered and impairment was found on the Impairment Index, Trails A, Digit Symbol, Seashore Rhythm and Speech Sounds-Perception Tests. In addition, subjects reported personality change and decreased memory.
Neurological abnormalities in a group of organophosphate-exposed subjects were described using the Halstead-Reitan Battery (31). Visual retention, memory dysfunction, and constructional deficits were reported (32).
Studies on chlorinated hydrocarbon solvents have also shown adverse effects. Trichloroethylene in low concentrations and for relatively brief times can lead to significant and prolonged impairment (33). Psychomotor speed and memory were two of the areas most affected, with the memory impairments characterized by storage and retrieval difficulties.
Neuropsychological changes have been found among community residents living in a supposedly benign environment such as areas adjacent to a wood-treating plant (34). Of the 34 subjects tested, more than 40% had sensory impairments, 86% had motor or psychomotor speed problems, and 72% had concentration difficulties. Disturbed autonomic function has been reported with chemical sensitivity (35), and abnormal neurocognitive function with chemical sensitivity/cacosmia (36).
Chemical sensitivity has been reported in the literature following exposure to chlordane (14), chlorpyrifos (37), pesticides (38), formaldehyde (39), tight or sick buildings (15), and organophosphates and solvents (40). These chemicals are not structurally related, although all may form free radicals and cause tissue damage.
A wide range of neurologic abnormalities [single photon emission computed tomography (SPECT), nerve conduction, electro encephalograms (EEGs), evoked potentials, neurocognitive] have been reported in chemically sensitive patients (41-43). Since depression and mood swings can occur with solvent/hydrocarbon exposures and with porphyrin disturbances, these are not in themselves evidence of a psychologic etiology of MCS (40). These and other studies strongly suggest that chemical sensitivity is a physiologic not a psychologic disorder (35,36,44).
A 1994 study found that 67% of patients with fibromyalgia and the same percentage with chronic fatigue syndrome (CFS) reported that their symptoms worsened on exposure to gas, paint, or solvent fumes, and 46 to 64% of these groups reported sensitivities to three other categories of common chemical exposures (45). Fibromyalgia patients have shown reduced current perception threshold (46) and T-cell changes (47). Chronic fatigue syndrome patients often meet criteria for fibromyalgia (48) and have impaired NK function, increased TA1/CD26, altered CD8, impaired mitogenesis (49,50), and vestibular and other neurologic abnormalities (51). Both chemical sensitivity (52) and chronic fatigue syndrome (53) have been postulated to involve limbic encephalopathy.
We describe medical findings on history, physical exam, and laboratory testing for patients who, in the wake of chemical exposure, developed chronic illness with multi-systemic symptoms exacerbated by exposures to multiple different chemicals at levels usually tolerated by most healthy members of the general population and previously tolerated by the patient.
Ziem's medical practice has been evaluating and caring for patients with MCS accompanied by chronic illness for many years, assisting them with environmental controls to reduce exposure and addressing clinical issues related to their exposure. Typically, an initial evaluation requires 1.5 to 2 hr for medical and exposure history, physical exam, evaluation of environmental aggravating factors, recommendations for environmental controls, and otherwise addressing clinical problems. Follow-up evaluations usually require 1 to 1.5 hr. This time-intensive approach to the evaluation of chemically injured patients contrasts with what we consider to be a too-cursory assessment prevalent among many industrial and academic professionals. We do not believe it is possible to evaluate and manage these disorders adequately in the 10 to 30 min usually allotted to such patients.
In the late 1980s, Ziem introduced a standardized questionnaire for initial patient assessment to evaluate the types of symptoms present, possible organ systems involved, and the types of chemical exposures perceived by these patients to be aggravating their symptoms. The full questionnaire is 16 pages long with 46 detailed questions. Reported here are the responses to questions 14 and 6 (Appendices 1 and 2) from 91 chemically sensitive patients whose first visit occurred after the introduction of the questionnaire. These two questions originally were developed by Dr. Ann Davidoff of the Johns Hopkins School of Hygiene and Public Health as part of a research project on chemical sensitivity (54).
Patients responding to the questionnaire came from many states from the eastern region of the United States, with most coming from the mid-Atlantic area. Most were referred by physicians not specializing in occupational medicine or toxic substances. Some were referred by patient support groups, friends, or relatives, and a few were legal referrals (although we have no data on the actual number in each category). Most but not all patients were well before the onset of their MCS. Former psychiatric diagnoses and treatment were unusual rather than typical.
In following these patients over time, Ziem's clinical impression is that patient responses to these two questions seem to correlate well with the clinical severity of their symptoms: sicker patients appear to have more frequent symptoms and to be affected by more exposures. However, it was not possible for this presentation to confirm this clinical impression by comparing response rates to exposures with clinical outcomes. This would be useful for future clinical studies. Symptom frequency can also be studied as an indicator of clinical severity.
These patients filled out the questionnaires at or shortly before their first visit. Some had been using some environmental controls; others had not. Many but not all patients were aware of chemical sensitivity as a potential problem for them. To assess the frequency of 51 different symptoms commonly associated with MCS, patients were asked in question 14 to describe whether these symptoms occur daily to almost daily, several times a week, once a week, several times per month, once per month or less, rarely, if ever, or not sure. In the analysis below, daily or almost daily responses are combined with several times a week or more responses to obtain a total figure for frequent symptoms.
Figure 1. Relative frequency of select symptoms as reported by Ziem's MCS patients.
All patients reporting increased sensitivity to chemicals accompanied by chronic illness were included in this analysis. They typically had frequent recurring or chronic symptoms in more than one organ system for over 6 months before completing the questionnaire. For some items in question 14, responses were only available for 89 or 90 patients: the bar graph in Figure 1 shows the number of patients (n) answering for each question. Outcomes are reported as percentages of the total answering each item. The bar for each symptom displays separately symptoms occurring daily to several times a week (combined totals from the first two columns from Appendix 1) and once a week to several times a month (combined totals from columns 3 and 4 from Appendix 1). These percents are then added to show the total percent with symptoms several times a month or more (this percent figure is shown to the right of first bar for each symptom). As an example, 57% of patients had headache daily to several times a week and 18% had headache weekly to several times a month--a total of 75% of patients experiencing headache several times a month or more.
Question 6 of the questionnaire, taken from the Davidoff study of MCS patients conducted at Johns Hopkins (54), has two parts. In the first part, patients were asked if they thought they would be sick following a 20-min or a 4-hr carefully defined exposure to a variety of common petrochemicals and irritants (Figure 2). In the second part of the questionnaire, they were asked if their symptoms would be exacerbated by a different set of briefer exposures (Figure 3).

Figure 2. Comparison of sensitivity to select exposures after 4 hr and 20 min as reported by Ziem's MCS patients.

Figure 3. Sensitivity to other select brief exposures as reported by Ziem's MCS patients.
Laboratory testing was recommended for most patients, more so in recent years as knowledge of MCS-related abnormalities grew. A few patients have had EEG, quantitative electroencephalogram, nerve conduction studies, SPECT scans, etc., but these data are not reviewed here because of the small numbers involved [and because these abnormalities in MCS patients have been reported elsewhere (42)]. Also, for all testing, financial constraints were often operative: disabled patients without adequate insurance were less able to afford testing. As a result, it is possible that tested patients were less severely affected than untested patients.
Immune testing was recommended for nearly all patients after the practice reviewed immune results in the late 1980s on six chlordane-exposed patients all showing increased activation and/or autoimmunity to evaluate whether the symptom of sensitivity to chemicals was accompanied by objective immune changes. Once it was determined that neurocognitive changes could be documented in MCS patients, those patients who described frequent impairment in thinking, concentration, and/or memory were referred for neurocognitive evaluation. Patients were referred for porphyrin testing beginning in 1995 if they had a history of brown or red urine not due to blood, or two or more porphyrialike symptoms such as abdominal pain with exposure, skin symptoms with sunlight, symptoms with fasting or skipping meals, or skin symptoms with exposure to metals. Thus, testing followed the usual clinical pattern of evaluation of patients more likely to be abnormal rather than a research pattern of testing every patient.
The practice has extensive data on immune testing, including testing of autoimmune parameters, immune activation, and T-cell subsets. The different normal values for CD4 and CD26 for the two different labs probably result largely from only one [Immunosciences Laboratory (ISL), Beverly Hills, California] of the two labs using flow cytometry. These immune tests were first done using the Antibody Assay Laboratory (AAL) in Santa Ana, California (for 68 patients) and, more recently, the ISL (for 23 patients). The latter laboratory also included tests of T- and B-cell function, which were not requested of the AAL.

Beginning in 1995, MCS patients with neurological and/or cutaneous symptoms suggesting porphyrin disorders have been screened for the various biomarkers of those conditions that may be detected in blood, urine, and stool. Samples were collected locally by independent laboratories and sent for analysis (via overnight delivery) to the Mayo Medical Laboratories in Rochester, Minnesota. Mayo was selected both because of its excellent reputation and because it offers more porphyrin-related tests than any other commercial laboratory in the United States. A full panel includes tests for five of the porphyrin-related enzymes involved in the heme synthesis pathway [aminolevulenic acid dehydratase (ALA-D), porphobilinogen deaminase, also known as uroporphyrinogen I synthase, uroporphyrinogen III cosynthase, uroporphyrinogen decarboxylase, and coproporphyrinogen oxidase], -aminolevulinic acid in urine, porphobilinogen in urine, quantitative urinary porphyrins, and fractionated fecal porphyrins. Results are presented for six MCS patients from Ziem's practice who have undergone all these tests and eight others who have undergone most of them (Table 1). Data on the three other patients screened are not included, as they each had undergone only one or two of the recommended tests, although two patients showed some abnormalities--one with decreased coproporhyrinogen oxidase (but no urine or fecal testing) and one with increased urinary coproporphyrins (but no blood or stool testing). In terms of both symptoms and history, the patients tested for porphyrin disorders were fairly representative of all chemically sensitive patients in this medical practice and none were known to have any other disorder associated in the literature with abnormal porphyrin metabolism (such as lead poisoning, hepatitis C, or liver cancer).

Patients diagnosed with MCS and describing difficulty with thinking, concentration, and/or memory were referred for neurocognitive testing. Those who live near Baltimore, Maryland, were referred to Dr. James McTamney, a clinical psychologist. As of September 1995, 13 patients had completed testing with Dr. McTamney. Patients in other geographic areas sometimes went elsewhere for testing, but because testing approaches and the tests used were different, these patients' data are not analyzed here. Dr. McTamney's evaluation included the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Table 2) and the Halstead-Reitan Battery (Table 3). The Halstead-Reitan Neuropsychological Battery is generally conceded to be a reliable psychological means of identifying patients with brain damage. It is an individually administered battery composed of the following tests: the Category test, the Tactile Performance test, the Seashore Rhythm test, the Speech Sounds Perception test, the Finger Oscillation test, and Trails A and B.

The Category test is a complex test of new problem solving, judgment, abstract reasoning, concept formation, mental flexibility, and mental efficiency. It requires a number of higher order functions such as the ability to note similarities and differences among stimuli and to formulate hypotheses regarding the principle that determines the correct answer. It is also a test of learning ability utilizing nonverbal material. Finally, there is a memory component to the test that requires the person to remember which principle was correct in determining the answer to an individual item. This requires a longer recall of previously learned correct responses.
The Tactile Performance test is a complex test requiring the individual to sustain adequate strength and speed of movement. It also requires the tactile perception and the ability to form a visual map of the board. The person, while blindfolded, must place ten blocks with the dominant hand on the first trial and then ten blocks with the nondominant hand on the second trial. On the third trial, the individual is allowed to use both hands together. After the trials are completed, the blindfold is removed and the person asked to draw the blocks approximating their size, shape, and relationships to one another while the blocks are out of sight.
The Seashore Rhythm test requires the individual to listen to 30 pairs of rhythmic beats from a tape recording and to select the proper response on an answer sheet as to whether the two tones in each pair are the same or different. The test requires the individual to discriminate between different patterns of nonverbal sounds while maintaining attention and concentration throughout the test.
On the Speech Sounds Perception test, the individual has a sheet of paper on which 60 groups of four nonsense words are listed. The individual must underline the correct response after hearing it on the audio tape recording.
On the Finger Oscillation test, the individual is required to tap as rapidly as possible with the index finger on a small lever attached to a mechanical counter. The person is given five consecutive 10-sec trials with the preferred hand and then five consecutive trials with the nonpreferred hand. The scores in this test are the average number of taps in a 10-sec period for each hand. The cutoff point indicating impairment would be less than 50 taps per hand on average.
Trails A and B do not contribute to the Halstead Impairment index but are considered a part of the Halstead-Reitan Battery. On the Trails A, the person is required to connect 24 numbered circles distributed in a random pattern while being timed for the performance. On Trails B, the person is required to connect circles numbered 1 through 13 and letters A through L alternating from number to letter in sequence.
The overall impairment index is calculated as the number of subtests within the impaired range divided by the overall number of subtests taken.
WAIS-R is a scale of an individually administered composite of tests in battery format. For all but the most severely impaired adults, a WAIS-R battery constitutes a substantial portion of the test framework of the neuropsychological examination. Eleven different subtests make up the WAIS-R battery. Six of the subtests are classified as verbal tests: Information, Comprehension, Arithmetic, Similarities, Digit Span, and Vocabulary. Five are termed performance tests and measure nonverbal/visuospatial factors. The tests are Digit Symbol, Picture Completion, Block Design, Picture Arrangement and Object Assembly.
We invite independent scientific review of our actual clinical data to further understanding of these patients' chemical injury and chemical sensitivity.
The vast majority of these patients reported some symptoms occurring daily to almost daily (Figure 1). Symptoms that could reflect respiratory responses to irritant exposures were frequent (several times a week or more): patients indicated nasal symptoms (60%), sinus discomfort (48%), throat discomfort (53%), weak voice/hoarseness (44%), chest tightness (42%), and wheezing (25%). The higher percentages of patients reporting nose and throat symptoms suggest that irritant effects may be greatest in the upper respiratory tract--areas that first encounter respiratory irritants (nose, throat, etc.)--and less as these irritants move down the respiratory tract. This is consistent with partial irritant removal as the inhaled air moves down the respiratory tract.
Frequent symptoms that suggest neurologic involvement were reported by many patients: tremor or shaking (29%), muscle twitching (33%), memory problems (67%), slurred words/difficulty finding words (58%), coordination difficulties (49%), and reduced bladder control (27%). The latter suggests possible involvement of the autonomic nervous system, as do some other frequently reported symptoms such as flushing skin (39%), rapid pulse (24%), palpitations (25%), reduced cold tolerance (31%), and reduced heat tolerance (24%). Based on patient exams and Holter monitoring, ectopic heartbeats appear more frequently during exposures and in sicker patients, but these data have not been analyzed in the aggregate. Mitral valve prolapse, a probable autonomic disorder, appeared to be unusually common in our chemically sensitive patients, possibly 10% or more, but this too has not been quantified in the aggregate. Murmurs seemed to subside with clinical improvement in some cases.
Symptoms of sensory organs were also reported to be frequent by a significant percentage of MCS patients: changes in hearing (32%), visual changes (48%), and ringing ears (36%). (Clinically, visual changes usually involve blurred vision with exposure.) Symptoms suggesting inflammation such as swollen glands, muscle discomfort/spasm, and joint discomfort also were commonly reported to be frequent by 21, 49, and 52% of patients, respectively. Frequent abdominal discomfort was experienced by 40%, consistent with abnormalities in porphyrin metabolism, as described below. Headache and unusual fatigue were frequent in 57 and 69% of patients, respectively. The 40% reporting frequent unusual thirst was an unexpected finding and may indicate endocrine changes in this group. The finding of significant musculoskeletal aching and fatigue among MCS patients is interesting in light of the overlap in symptomatology and clinical findings between MCS, fibromyalgia syndrome, and chronic fatigue syndrome (45).
In response to question 6 (Figure 2), more than two-thirds of the patients reported symptoms with exposure to combustion products such as passive cigarette smoke and vehicle exhaust and to many other frequently encountered indoor and outdoor petrochemical air pollutants (new carpets, pesticides, paint, scented products, etc.); half or more of the patients reported symptoms when exposed to other irritants such as detergents or chlorine. In this group of patients, the vast majority who reported symptoms with 4-hr exposures also experienced symptoms with only 20-min exposure. This has implications for reasonable accommodation: requiring daily commuting, work, or even brief meetings in newly carpeted, remodeled or recently pesticide-treated areas could aggravate symptoms in a significant proportion of persons with chemical sensitivity. It also suggests that many current products and practices involving chemicals (remodeling, cleaning, repairs, pesticide application, etc.) present frequent problems for these patients.
Ziem first encountered cellular immune abnormalities while evaluating a cluster of eight chlordane-exposed patients with chemical sensitivity in the late 1980s. She has checked for similar immune abnormalities in other chemically exposed patients with chemical sensitivity, using the AAL for testing on the first 68 patients (Table 4).
Compared to lab normals, the majority of those tested by AAL had increased total CD26 (also known as TA1) cells, which is considered a marker of immune activation (55). Seventeen (25%) had increased CD4 (helper T lymphocytes). Only five had increased CD8 (suppresser T lymphocytes). NK (CD57) evaluations were done on only 15 patients but were reduced in number in 5. B lymphocyte (CD14) values are available for 57 patients; these were reduced in 18 (32%) and increased in 1 patient. Judgments of abnormal and normal ranges were made by the laboratory, but the raw data and the laboratory's normal reference ranges are provided for independent review.
Autoantibodies were evaluated and found to be present in increased titer in some cases: antimyelin (nervous system) autoantibodies and antismooth muscle (liver) in about half the patients, with antiparietal (stomach), antibrush border (kidney), antimitochondrial, and antinuclear in only a small number of patients.

Re: CFS, MCS, LGS, & SR. WOW !

Posted by Cont on March 15, 1999 at 21:51:46:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by Profile - Ziem on March 15, 1999 at 21:46:35:

Compared to lab normals, the majority of those tested by AAL had increased total CD26 (also known as TA1) cells, which is considered a marker of immune activation (55). Seventeen (25%) had increased CD4 (helper T lymphocytes). Only five had increased CD8 (suppresser T lymphocytes). NK (CD57) evaluations were done on only 15 patients but were reduced in number in 5. B lymphocyte (CD14) values are available for 57 patients; these were reduced in 18 (32%) and increased in 1 patient. Judgments of abnormal and normal ranges were made by the laboratory, but the raw data and the laboratory's normal reference ranges are provided for independent review.
Autoantibodies were evaluated and found to be present in increased titer in some cases: antimyelin (nervous system) autoantibodies and antismooth muscle (liver) in about half the patients, with antiparietal (stomach), antibrush border (kidney), antimitochondrial, and antinuclear in only a small number of patients. AAL considered myelin antibodies abnormal if titers were over 1.8; other autoantibodies were considered abnormal if titer levels were 1:20 or greater. Exact titer levels were not reported (by AAL) but may have provided additional information. Ziems's clinical impression is that as patients improved, some titers fell within the laboratory's normal range, but longitudinal data have not been quantified in aggregate. Titer levels facilitate comparison of changes in clinical status with increase or decline in titer levels. The striking proportion with autoantibodies against liver and nervous system tissue (about half the total patients tested for each) is consistent with neurologic effects and liver involvement, which is consistent with porphyrin disturbance.
Table 4 also lists the location, situation, and chemical(s) involved in each patient's presumed causal exposure when this could be determined. An exposure was considered causal for this purpose if: there were no symptoms of multiple chemical sensitivity accompanied by chronic illness before the exposure; significant symptoms occurred during or shortly after the exposure (within days); symptoms improved away from the exposure on at least two occasions; and symptoms recurred on reexposure on at least one occasion. For any particular products associated with causal exposures, the chemicals involved were identified whenever possible, usually from material safety data sheets.

Over half the patients listed in Table 4 were considered occupational in probable causal exposure: 23 in the private sector (OCP in Table 4) and 14 in government or the public sector (OCG). Many public-sector exposures appeared to involve tight buildings. Public sector reluctance to tackle the chemical sensitivity problem might be affected by a substantial number of compensation cases filed by public sector employees. School exposures accounted for eight cases, all involving pesticides, and primarily affected students. Home exposures involved over a fourth of the total cases seen by Ziem. Nearly a third of all cases were felt by Ziem to be caused by pesticide exposure.
After Simon raised questions about the reliability of AAL testing in April 1994--he said the results of split samples secretly submitted to the laboratory showed that "the reliability on most of their measures is no better than chance" (56)--Ziem arranged for subsequent immune function testing to be performed by the ISL. In this presentation of ISL data, both normal and abnormal results are shown but only for those particular tests done on more than half the patients (Table 5). The only ISL data excluded after analysis are those on MY, GP, SG, and AS neural autoantibodies, each of which were tested in less than five patients, although some other parameters were not analyzed for this paper.

Autoantibody levels were normal for most antigens, but 7 of 21 showed increased levels compared to laboratory normals for both rheumatoid factor and total immune complex. Patients tested through ISL typically had normal numbers of total helper and suppresser cells (CD4, CD8) and normal CD26 (TA1) cells. Results from the two laboratories may have differed because of different normal ranges, different patients being tested, and/or techniques; this merits further study. However, abnormalities in ISL tests did include higher than expected levels of chemical antibodies (11 of 24 patients), typically involving benzene, which is most likely encountered as a metabolite of aromatic petrochemicals. Reduced T-cell function was common (9 of 21 patients tested), with 7 of the 9 being abnormal using both concanavalin A (conA) and phylohemagglutinin (PHA), an indication of intratest consistancy. Impairment of B-cell function was seen in five patients, of whom four were abnormal in all three tests (pokeweed mitogen, lipopolysaccharide, Staphalococcus aureus). This consistency across tests increases the likelihood of their validity. While the measure of total NK cells was typically normal, function was impaired in 14 of 22 tested patients.
Immune indicators are likely to change significantly over time following exposure, with initial activation leading to a cascade of other immune changes and later resolution of activation. Thus, single immune measurements in a population with varying time intervals following various causal and significant aggravating exposures are likely to obscure certain abnormalities. The optimal way to study immune changes is to observe patients shortly after casual exposure and to follow them through time. The time interval to maximum immune activation and other immune responses and to return to preexposure levels, if ever, at this time is not known for chemically sensitive patients. Further, different immune measures are likely to peak at different time intervals following onset of illness.
For a patient whose chemical sensitivity was thought to be caused by occupational exposure to carbonless copy paper, we compared immune measurements before the patient left and after she returned to her job, which required sitting near and working with large quantities of carbonless copy paper (Table 6). These data suggest that immune measures pre- and postchallenge testing are unlikely to show major changes. The patient had been away from exposure for many months and showed significant clinical improvement. Chemical sensitivity has been seen in a hundred patients with substantial occupational exposure to carbonless copy paper (E Panitz, personal communication).

In 1994, a few physicians began testing for porphyrin disturbances in chemically injured patients previously diagnosed with MCS. Like patients with some types of congenital porphyria, chemically sensitive patients frequently describe intolerance to small amounts of alcohol and many synthetic (petrochemical) medications, ingestion of which provokes acute outbreaks of neurological and psychological symptoms such as imbalance, tremor, abdominal pain, and mood swings as well as symptoms or signs of autonomic involvement such as rapid heart rate and increased blood pressure. Patients also sometimes exhibit cutaneous symptoms of photosensitivity such as skin rashes and other lesions.
Intrigued by informal reports of porphyrin abnormalities being found in over 70% of MCS patients being tested (57), Ziem and her research associate, Albert Donnay, developed a protocol for diagnosing disorders of porphyrin metabolism in chemically sensitive patients to try to control for the many variables that may affect testing for porphyrins and related enzymes (58). The protocol was developed in consultation with the porphyria laboratory of the Mayo Medical Laboratories and is based on Mayo's 1995 test catalog and its 1994 interpretive handbook. The protocol includes a one-page patient testing questionnaire (Appendix 3), most of which has been incorporated into the Health and Environmental History Questionnaire. It was surprising to learn from this questionnaire and verbal interviewing that even dark brown or red urine (not attributable to blood) was relatively common in MCS patients during more severe episodes of illness.
It appears that most of the patients questioned experienced significant porphyrialike neurological reactions (including sharp abdominal pain) when exposed to such well-known porphyrogenic stressors as alcoholic beverages (even a single drink was enough to trigger symptoms), usual therapeutic doses of many synthetic pharmaceuticals, and fasting or skipping meals. Most of those with skin symptoms also reported adverse reactions to sunlight exposure.
It was found that because of problems with memory, concentration, and general fatigue, patients often experienced difficulty understanding and following the necessary instructions. A separate patient testing questionnaire provided a double check on such compliance (Appendix 3). Since many biomarkers of neurological and neurocutaneous porphryinopathy commonly are known to be abnormal only during periods of acute attack, patients usually were advised to wait for testing until their symptoms were "worse than usual." Unfortunately, many went for testing without waiting for an exacerbation of their illness. Of the two biomarkers in urine associated with acute attacks of neurological congenital porphyrias, porphobilinogen was normal in 10 of 11 patients tested, and *-aminolevulinic acid was normal in 7 of 8 tested. Despite lacking these indicators of acute attack, surprisingly 12 of the 14 nevertheless tested positive for a variety of other porphyrin-related abnormalities (defined here as any result outside Mayo's range of normal).
Of the 13 patients tested for 5 different urinary porphyrins, 8 had at least one abnormality. Four patients had only elevated coproporphyrins, 1 had only elevated pentacarboxylporphyrins, 2 had elevations in both of these, and 1 had elevated coproporphyrins and uroporphryins. Of the 11 patients with stool evaluations, 3 showed abnormalities: 1 had only elevated coproporhyrins, 1 had only elevated protoporphrins, and the third patient had elevated copro-, uro- and protoporphyrins. Those with elevated fecal coproporphyrins also had elevated urinary coproporhyrins. One patient submitted a stool specimen that Mayo felt was too small to represent a 24-hr sample, so this result was not included.
All patients were given blood tests for the activity of porphyrin-related enzymes. The most common enzyme deficiency was in the activity of coproporhyrinogen oxidase (CpgO), which was below normal in 9 of the 14 patients tested. CpgO was evaluated in reticulocytes in conjunction with a reticulocyte count which, because of lab confusion was done in most but not all patients. When completed, the reticulocyte counts were normal. The activity of both ALA-D and porphobilinogen deaminase (PbgD) was below normal in 7 of the 14 patients. Uroporphyrinogen decarboxylase and uroporphyrinogen III co-synthase activity was tested in 12 and 14 patients, respectively, and found to be normal in all cases. Only two patients had no enzyme deficiencies; four had one deficiency each, four had two each, and four had three each (ALA-D, PbgD, and CpgO). The enzymes affected here occur in cytosol and mitochondria (59), and the presence of disturbed enzymes in both these compartments suggests chemical injury to both mitochondrial and cytosol cellular areas.
Despite lack of a control group, it is difficult not to conclude that porphyrin disturbances are present in a substantial percentage of chemically sensitive patients. The multiple enzyme deficiencies found in many of these MCS patients (6 of 14) are not characteristically associated with any of the known types of congenital porphyria, which usually are marked only by a single enzyme deficiency or with secondary coproporphyrinuria due to other unrelated conditions, usually an isolated abnormality, unaccompanied by enzyme deficiencies. (Because of testing techniques at Mayo, when porphobilinogen deaminase is reduced, ALA-D can also appear to be reduced, so the presence of these two abnormalities together cannot be presumed to involve two enzymes.) Given also that none of the patients tested had known family histories of active or latent porphyria, the fact that such relatively rare abnormalities and porphyrialike symptoms were found in 12 of 14 patients strongly suggests that those with MCS suffer from an environmentally acquired rather than an inherited disorder of porphyrin metabolism. (A genetic predisposition cannot be ruled out conclusively without further testing the patients and family members, but statistically such a finding is highly unlikely, since congenital porphyrias are so rare.)
Although the porphyrin disturbances and enzyme deficiencies found in these MCS patients appear to be milder than in the acute types of congenital porphyria that primarily affect heme synthesis in the liver, other organs clearly are affected in cases of toxic exposure and chemical injury (e.g., irritant effects on the respiratory system, petrochemical neurotoxicity, immune dysfunction). These factors together with the involvement of multiple enzyme deficiencies may account for the somewhat more diverse symptomatology seen in MCS patients compared to those with strictly congenital porphyria. This certainly is the case with other toxically acquired porphyrinopathies such as the well-recognized forms caused by overexposure to lead, dioxin, and hexachlorobenzene, all of which, as neurotoxins, affect more than just heme synthesis and cause chemical injury unrelated to porphyrin abnormalities. Given all the above, it is not unreasonable to suspect that the different patterns of porphyrinopathy evident in MCS patients may be caused and/or exacerbated by these patients' own unique overexposures to specific toxic chemicals.
On the WAIS-R neuropsychological evaluation done by McTamney (Table 2), 6 of the 13 MCS patients tested showed a significant difference of 15 points between the verbal and performance phases of the test, all scoring higher on the verbal portion. Only one patient scored in the superior range for IQ with no apparent difficulties.
The Halstead-Reitan battery showed a number of significant scores indicating impairment (Table 3). On the Category test, 53% of patients scored in the impaired range. On the Tactile Performance test, 60% scored in the impaired range on the total time required to complete the three trials. None of the patients had problems with the dominant hand, while 30% were slower with the nondominant hand despite the previous trial with the dominant hand. Twenty-three percent of patients scored in the impaired range on the memory phase of the Tactile Performance test, while 84% scored in this range on the Localization Scale.
The Rhythm Test showed 53% in the impaired range, whereas the Speech Sounds Perception Test showed 46% in the impaired range. On the Finger Oscillation Test, 53% scored in the impaired range with the dominant hand and 61% for the nondominant hand. Trails A had 53% in the impaired range, whereas Trails B showed 61%. The overall Impairment Index scores showed 53% impairment. The most common neurologic changes on the physical exam were reduced vibratory perception (hands) and abnormal Romberg (suggesting vestibular neuropathy).
Chemically sensitive patients from a medical practice, who often have experienced different initiating exposures, may have different patterns of porphyrin disturbance, as was found in this study. This is the pattern to be expected from the literature on acquired porphyrin disturbance. Future research on porphyrin abnormalities should compare results by type of original exposure and by type and level of current symptoms, with patients tested consistently during both acute and nonacute phases.
Discrepancies are found between our immune testing results and those of Simon et al. (60). Simon found significantly lower TA1/CD26 cell activation among MCS patients compared to that of a group of controls from a musculoskeletal clinic, whereas our results from AAL and the literature show higher values compared to those of normal reference ranges following chemical exposure. It is possible a coding error occurred in the Simon study; raw data should be made available to independent researchers. Ziem personally coded immune data for Table 4, but it could also be independently reviewed. Since both studies used AAL, this extent of discrepancy is unexpected.
Other confounding problems exist with the Simon data, which is often cited because it uses a control group. However, the control group is problematic in the Simon study because it consists of patients seen in a musculoskeletal clinic who were not screened for MCS, chronic fatigue syndrome, or fibromyalgia. The latter are both more common diagnoses whose symptoms have been found to overlap those of multiple chemical sensitivity (and of each other) so as to be almost indistinguishable in as many as 67% of all cases (45,61). Musculoskeletal controls certainly would be expected to include patients with inflammation of joints, muscles, and/or connective tissue in whom cellular immune changes of inflammation also could be present. In addition, these controls are likely to be taking medication for pain, a frequent reason for clinic visits in such patients. Patients taking medication for pain are not an appropriate control group for neurocognitive test comparisons, which also were reported in this study. We believe the clinical records of Simon's control patients should be independently reviewed to evaluate for fibromyalgia, chronic fatigue, chemical sensitivity, inflammatory processes, and use of pain medication.
Both the control and study groups' raw data for the TA1/CD26 parameter also should be independently reviewed. Simon attributes his study's unusual immune findings to the laboratory's poor reliability, which he asserts is "no better than chance on most of their measures," but he also admits that these critical data on test reproducibility were not published in his paper (56). Given these problems, and the reports of immune abnormalities here and by other authors, it appears that the issue of cellular immune disturbance in chemically sensitive patients needs further study.
Immune response probably varies greatly with time and appears to differ with different types of exposures. Immune studies should evaluate exposed individuals over time, beginning as soon as feasible after causal exposures and following for several years. Major immune changes may not be seen following acceptable challenge doses; the patient whose immune measures increased mildly to moderately with return to workplace exposure (Table 6) had serious exacerbation of many clinical symptoms lasting several months. This level of exposure with accompanying symptoms would not be acceptable as a clinical chamber challenge.
Failure to follow chemically sensitive patients over time leads to lack of understanding of responses to exposures and of removal from exposure. We are following more than 300 chemically sensitive patients and have observed both significant clinical improvement with reduced exposures and clinical exacerbation on reexposure (including increased abnormalities on exam and laboratory testing). This is a clinical impression, although it is not quantified in aggregate for this paper. It appears that to date the professionals who have published studies suggesting a psychological origin of chemical sensitivity do not follow these patients over time, do not remove them from exposure and observe responses and then return them to exposure and observe responses. Also, these researchers are not physicians treating patients for the disorder, and therefore are not able to observe the ongoing clinical course of the illness.
We reported onset of chemical sensitivity shortly following exposure to a wide variety of petrochemicals, combustion products, and irritants (Table 4). In some cases these were discrete events such as leaks, spills, or other acute exposure events. Often, especially in occupational settings, exposures were chronic. Typically, in these situations the illness began as a more limited sick-building syndrome, which with further exposure developed into chronic illness with associated chemical sensitivity. This suggests that exposure controls in the early phase may prevent the more disabling phase, and that sick-building syndrome is a more self-limited form of chemical sensitivity.
The combined abnormalities of the immune, respiratory, porphyrin, and nervous systems discussed here are incompatible with a psychologic etiology for chemical sensitivity. A systematic review of ten recent studies purporting to show a psychologic origin for chemical sensitivity revealed serious methodologic flaws in all studies including the Simon study, sufficient for the reviewing authors to conclude that none of the studies had the methodologic strength to determine that chemical sensitivity was psychologically induced (40).
Vasospasm appears to be a problem in chemically sensitive patients. Most of our patients noted frequent headaches that often were consistent with migraine and diagnosed as such by other evaluating physicians. Migraine is known to be triggered by chemical odors (62) and involves abnormal vasospasm. Cerebral vasospasm with reduced cerebral blood flow has been reported with encephalopathy following solvent exposure (63) and in patients with chemical sensitivity (42,64,65). One of our patients developed new onset of Raynaud's phenomenon (a vasospastic disorder), which we observed to be triggered by double-blinded finger contact with carbonless copy paper (the probable cause of her chemical sensitivity). Only a few patients developed new onset of high blood pressure (another vasospastic response), which is seen primarily following exposure (their blood pressure readings usually remained normal between exposures). These vasospastic responses may involve abnormal autonomic function, which has been observed to occur with chemical sensitivity (35).

Diagnoses of fibromyalgia and chronic fatigue syndrome are common among our MCS patients (currently 75 and 85%, respectively). We recommend further research on the incidence of chemical sensitivity in these groups using the types of screening questionnaires developed by Kipen, Bell, and Davidoff. If these disorders are essentially the same, much of the research already done for fibromyalgia and chronic fatigue syndrome may also apply to MCS; this could reduce research costs and time delays. Increased sensitivity to chemicals also occurs with migraine, asthma, and other disorders. However, fibromyalgia syndrome, chronic fatigue syndrome, and porphyrin disorders are multiple-system disorders involving chemical sensitivity.
Over one-third of our patients described tremor several times or more a month (Figure 1). Several patients were told by other physicians that they were developing Parkinson's disease during more serious periods of their illness only to have the diagnosis rescinded when they improved after environmental controls were put in place to reduce exposures. Parkinson's disease has been reported following pesticide exposure (66).
Nearly half our patients reported increased symptoms during or after swimming in a chlorinated pool (Figure 3), which has been associated with increased chloroform levels (67). Patients also often reported reduced symptoms during and after showering with, compared to without, an activated charcoal filter that helps remove chloroform. Longer showers and/or those with greater flow rates release more chloroform and other chlorinated products. Water filters that reduce chlorine therefore appear to be a reasonable control for MCS.
In addition to filters for chlorinated water, other reasonable means exist to control exposures that aggravate MCS symptoms. Aggravation from vehicle exhaust (Figure 2) can be reduced by using an auto filter device that provides activated charcoal filtration and by avoiding ozonating devices which generate irritants. Symptom exacerbation from pesticides, cleaning products, building materials, etc. can be reduced by using less toxic products. Reasonable accommodation at the work place, at home (apartments, condominiums, etc.) and at school and public areas could be available to those with this debilitating condition by requesting that less toxic products and procedures be used. Further helpful suggestions are discussed in our Environmental Control Plan (68).
In our 10-year experience with chemically sensitive patients, no patients lost their sensitivity to chemicals. No patients were able to go to problem environments (new carpets, recent pesticides, etc.) consistently without deterioration of their conditions. Thus, MCS should be considered a permanent condition. Some patients were able to continue working if their employers provided nontoxic accommodations for their conditions. More than half the patients continued to be too sick to work under the prevailing conditions at the work place. We believe this proportion could be reduced if society pays more attention to use of nontoxic products.
The large and growing epidemic of chemical sensitivity in the United States is partly because of inadequate exposure limits for chemicals. These exposure limits have been shown to lack scientific merit (69) and to have been seriously influenced by vested interests (70-73). Exposures that cause MCS at home or the work place sometimes reflect relatively widespread practices or products, some of which may be within legal limits. Many aggravating exposures are probably below legal limits but often do not provide an adequate safety margins even for the healthy population (69). The widespread indoor use of pesticides in U.S. schools, homes, work places, and public buildings is in striking contrast to practices in Germany and Scandinavia. Major policy changes with regard to chemical product formulation and use will be necessary to reduce future cases of permanent chemical sensitivity as well as to reduce disability for currently affected patients.
Most of our patients with symptoms of MCS appear to have developed chronic illness following exposure to petrochemicals, combustion products, and other irritants. Symptoms and signs in patients reporting chemical sensitivity suggest involvement of the immune, respiratory, limbic, and other nervous systems (central, peripheral, autonomic) as well as impaired porphyrin metabolism. This suggests that multiple mechanisms of chemical injury probably are involved, all of which can intensify response to an exposure. Immune activation, neurogenic inflammation (74), kindling (75), and/or time-dependent sensitization (76) can amplify the body's response to chemical exposure in the immune system, respiratory system, and nervous system. It is possible that impaired porphyrin metabolism reduces the amount of heme available for cytochrome P450, part of the liver's major detoxification system for foreign chemicals, which could result in intensified symptoms for a wide range of exposures.
Research strategies are needed that allow evaluation of multiple sites of chemical injury and multiple mechanisms of injury--almost all studies to date focus on only one type of chemical injury.
Immune activation also could lead to increased response to foreign substances, such as conventional allergens. We note in our patients an apparent high rate of new onset of allergies to mold, dander, etc., following onset of chemical sensitivity. Kipen reports what appears to be a significant level of sensitivity to chemicals among asthmatics (77). Asthma also is increased with higher levels of indoor volatile organic compounds (VOCs), formaldehyde and/or limonene (78). Persons with other allergic diatheses also should be studied for sensitivity to chemicals. If indeed chemical exposure via immune activation contributes significantly to the high and increasing rates of allergies, we may have the means to counter this alarming trend.
Studies of chemically injured populations should compare MCS patients with specific and identifiable initial exposures to MCS patients who cannot identify any specific triggering exposure. Other patient groups that should be studied for MCS include those with recurring migraines, chronic sinusitis or rhinitis, degenerative neurologic diseases (such as acute types of congenital porphyria), autoimmune disorders (such as multiple sclerosis, autoimmune hepatitis, rheumatoid arthritis, and lupus), hyperactive children, and patients with attention deficit disorder. Chemically exposed groups also merit study, especially those that have avoided further occupational exposures following work with pesticides, solvents, etc. We believe such studies will find levels of chemical sensitivity in these subpopulations that are considerably greater than currently recognized.

Appendix 1: Question 14 from Ziem's Health and Environmental History Questionnaire
Appendix 2: Question 6 from Ziem's Health and Environmental History Questionnaire
Appendix 3: Patient Testing Questionnaire from Protocol for Diagnosing Disorders of Porphyrin Metabolism in Chemically Sensitive Patients by Donnay and Ziem

Re: CFS, MCS, LGS, & SR. WOW !

Posted by References on March 15, 1999 at 21:53:16:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by Cont on March 15, 1999 at 21:51:46:

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Re: CFS, MCS, LGS, & SR. WOW !

Posted by BELL- neurogenic sensitization on March 15, 1999 at 21:58:28:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

Individual Differences in Neural Sensitization and the Role of Context in Illness from Low-level Environmental Chemical Exposures
Iris R. Bell,1,2,5 Gary E. Schwartz,1,2,3 Carol M. Baldwin,2,4 Elizabeth E. Hardin,1 Nancy G. Klimas,6,7 John P. Kline,2 Roberto Patarca,6 and Zhi-Ying Song2
Departments of 1Psychiatry, 2Psychology, and 3Neurology, and 4Division of Respiratory Sciences, University of Arizona, Tucson, Arizona; 5Department of Psychiatry, Tucson Veterans Affairs Medical Center, Tucson, Arizona, 6Department of Medicine (Immunology), University of Miami School of Medicine, Miami, Florida; 7Miami Veterans Affairs Medical Center, Miami, Florida

Multiple Chemical Sensitivity Clinical Observations That Require Explanation

Olfactory-Limbic and Neural Sensitization Model
Time-dependent Sensitization

Design Implications of Time-dependent Sensitization
Sensitizable and Previously Sensitized Individuals
Context-dependent and Context-independent Sensitization

Sensitization and the Adaptation Hypothesis

Time Factors in Experimental Approaches


This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena. -- Environ Health Perspect 105(Suppl 2):457-466 (1997)
Key words: adaptation, conditioning, dopamine, environmental chemicals, kindling, limbic, multiple chemical sensitivity, sensitization, tolerance
This paper is based on a presentation at the Conference on Experimental Approaches to Chemical Sensitivity held 20-22 September 1995 in Princeton, New Jersey. Manuscript received at EHP 6 March 1996; manuscript accepted 27 December 1996.
Supported by grants from the Environmental Health Foundation and the Wallace Genetic Foundation.
Address correspondence to Dr. I.R. Bell, Department of Psychiatry, Tucson Veterans Affairs Medical Center, 3601 S. 6th Avenue, Mail Stop 116A, Tucson, AZ 85723. Telephone: (520) 792-1450, ext 5127. Fax: (520) 629-4632. E-mail: ibell@ccit.arizona.edu
Abbreviations used: ADHD, attention-deficit/hyperactivity disorder; ASI, Anxiety Sensitivity Index; CNS, central nervous system; CS, conditioned stimulus; DA, dopamine; EEG, electroencephalogram; MCS, multiple chemical sensitivity; SCL-90-R, Symptom Checklist 90 (revised); TDS, time-dependent sensitization; TLE, temporal lobe epilepsy; UCS, unconditioned stimulus.
This paper outlines the possible relationships between the olfactory-limbic system and neural sensitization model for multiple chemical sensitivity (MCS) (1) and certain exposure-related symptoms; and discusses potential interactions between individual differences in neural sensitization, conditioning (context), and habituation (tolerance; adaptation) that might affect experimental design in MCS studies. We describe the model briefly, using data and conclusions from our laboratory studies on chemically sensitive human subjects to illustrate certain points. Research on chemically intolerant subjects thus far indicates that they a) exhibit bidirectional variability around an unstable set point (2) or failure of habituation over time; b) report certain lifetime patterns of medical (3-5) and psychiatric (6-9) conditions that require explanation in any MCS model; c) present more complex clinical phenomenology than chemical avoidance behaviors alone (3,4).
Multiple Chemical Sensitivity Clinical Observations That Require Explanation
It is essential to note that the clinical observations summarized below represent a mixture of anecdotal and controlled data from the published literature, with relevant citations. Much of the specific epidemiologic and laboratory study evidence needed to support particular points is not available. At the same time, these concepts represent a core of clinical information that requires articulation in order to design proper studies for testing the assumptions and various mechanistic hypotheses for MCS. MCS is a chronic, polysymptomatic condition. Affected individuals report recurrent flares of illness when exposed to low levels of environmental chemicals (e.g., pesticides, solvents), common foods (e.g., milk, chocolate, wheat, sugar), multiple drugs, and other ingestants (e.g., alcohol, chlorinated water) (10). Women represent 70 to 80% of the affected population (10). The illness process involves two steps: initiation and elicitation (10). Many (11), but not all (12), MCS patients report an identifiable, acute, or subacute exposure event in which they inhaled, absorbed, or ingested toxic levels of a particular chemical agent. Typically, the initiating substances are pesticides or solvents (4,5). Patients report recovery from the more classical, substance-specific toxic effects, followed by a deterioration in overall health over a period of weeks to months. Subsequent eliciting agents are numerous and diverse in chemical structures, but often similar in their adverse effects. Triggers can include previously tolerated levels of pesticides, perfumes, deodorizers, gasoline, paint, new carpet, fresh newsprint, or traffic exhaust, as well as foods, drugs, and alcohol (4). Patients report the ability to return to a relatively normal baseline if they avoid exposures to inciting agents (13). Some investigators postulate that adaptation to chronic exposures dampens the degree of reactivity to exposures under certain circumstances (5). They suggest that this adaptation necessitates removal from chronic exposures prior to acute sensitivity testing to avoid type II error (5,10).
Individual reactions to many chemically unrelated substances include cognitive difficulties with concentration and memory, neuromuscular, gastrointestinal, affective, musculoskeletal, respiratory, and cardiac dysfunctions, and fatigue (3,4,11,14). Miller and Mitzel (4) found that cognitive symptoms of MCS such as slowed thinking, memory problems, and concentration difficulty are among the most severe dysfunctions, whereas feelings of unreality/spaciness and lightheadedness are among the most frequent features of the condition (15). Symptoms of a given adverse reaction can begin within minutes or be delayed for up to 24 hr after a given exposure or ingestion (16). Once triggered, reactions last from minutes to several days, even if the exposure is terminated promptly (16). Different phases of the same reaction can involve activated states such as insomnia, anxiety, or irritability, and deactivated states such as sleepiness or depression in the same person, i.e., bidirectionality (5,10,16). MCS patients also report increased lifetime rates of physician-diagnosed rhinitis, sinusitis, menstrual disorders, irritable bowel, arthritis, migraine headaches, breast or ovarian cysts, depression, and panic disorder (3,6-8). MCS patients usually show marked avoidant behaviors toward inhaled chemicals (for which onset of adverse reactions is within minutes), but often extreme cravings for foods such as sweets (for which onset of adverse reactions is delayed by hours) (5). MCS reactions include somatic manifestations as well, involving autonomic dysfunction or inflammation at multiple sites (17-19).
A recent study indicated that MCS patients make an average of 23 health care provider visits per year (20). This poorly understood condition is costly in terms of worker's compensation, personal injury litigation, and health care utilization. Although definitive population-based studies have not been published, the estimated prevalence of MCS ranges from 0.2 to 4% of the general population (21,22). Morrow et al. (23,24) found that 60% of solvent-exposed industrial workers manifested symptoms of illness from chemical odor. Bell et al. (21,25-27) demonstrated less severe self-reported chemical odor intolerance in 15 to 30% of young adult college student (mean ages 18-19 years) and active retired community elderly (mean ages 68-76 years) samples. In contrast with MCS populations (3,4,6), neither the college students nor the elderly individuals with chemical odor intolerance worked in the chemical or associated industries or perceived themselves as disabled by chemical-related illness at the time of the study.
MCS is a complex condition that, once established, defies traditional dose-response relationships of toxicology. That is, in MCS, low doses trigger large responses. The symptom of illness from low-level chemical odors is common in populations not motivated by secondary gain in terms of worker's compensation or disability claims (22). The manifestations of adverse reactions are multiple and individualized, and often include involvement of the central nervous system (CNS) (3,4).
Olfactory-Limbic and Neural Sensitization Model
The olfactory-limbic and neural sensitization model proposes that individual differences in reactivity to environmental substances in MCS derive from neurobiologically based sensitization of the olfactory, limbic, mesolimbic, and related pathways of the CNS (1,28). The nose is a direct pathway into the limbic system both for neural signals (odor-olfactory and irritant-trigeminal) (29,30) and for transport of many molecules (31,32). Among the sensory systems, only the olfactory system lacks a blood-brain barrier (29,30). The olfactory bulb, amygdala, and hippocampus are interconnected parts of a phylogenetically older portion of the brain that is particularly vulnerable to sensitization processes (33,34). Repeated intermittent exposures to a given stimulus lead to progressively increased levels of responsivity over time in those structures (1,33,34). Sensitization then persists without reexposures for long periods of time. As a result, Stewart and Badiani (35) refer to sensitization as a basic form of learning and memory. Indeed, drugs that can interfere with the neurobiology of learning, such as excitatory amino acid antagonists or protein synthesis inhibitors, can also block acquisition of sensitization (36-38). The limbic region participates in regulation of a broad range of psychological and physiological functions, including anger, fear, learning and memory, reproduction, eating, drinking, autonomic activity, and pain (39-41). Limbic dysfunction could lead to polysymptomatic conditions involving neurobehavioral and somatic manifestations (1).
KindlingKindling is the prototypical sensitization process, in which a low-level electrical or chemical stimulus that initially had little or no effect on behavior eventually elicits persistent vulnerability to electrographic and behavioral seizures after daily repetition for 10 to 14 days (42). Kindling is considered an animal model for temporal lobe epilepsy (TLE) in humans. Full kindling is unlikely to provide an explanation for most MCS cases, as increased rates of TLE per se and other clinically obvious seizure disorders are not present in the majority of MCS patients. However, partial kindling to a point short of seizures produces persistent changes in electrical firing patterns and in aggressive and social behaviors of animals (43). Many environmental chemicals, especially pesticides (44-46) and the solvent toluene (34), induce chemical kindling or partial kindling, or facilitate electrical kindling of the amygdala in animals. Rossi (42) has recently published a detailed examination of the basic neurobiology issues in kindling as a model for MCS.
No studies have yet directly examined MCS patients for electrophysiological evidence of partial kindling, TLE (complex partial seizures), simple partial seizures, or subclinical seizure disorders. In view of the association of high rates of polycystic ovary disease in women with TLE (47), a history of ovarian cysts (3) could suggest focal amygdala or hypothalamic dysfunction resulting in reproductive hormone dysregulation in MCS patients. Moreover, Bell et al. have shown that young adults (48) and middle-aged women (49,50) with chemical odor intolerance have higher scores than do their chemically tolerant peers on the McLean Limbic Symptom Checklist. This scale is based on self-ratings of the frequency of ictal symptoms of TLE such as somatic, sensory, behavioral, and memory dysfunctions (51).
Several different studies have shown that MCS patients have an inordinately high rate of past or comorbid depression and panic disorder (6-8), conditions also associated with limbic system dysfunction. Notably, a subset of panic disorder patients with symptoms of derealization and other sensory distortions actually exhibit electrophysiological patterns of simple partial seizures (e.g., unilateral delta-theta slowing over temporal regions) during attacks in supermarkets and malls monitored with ambulatory electroencephalogram (EEG) (52). In addition, nasal inhalation of an olfactory stimulus odor (sweet orange in propylene glycol) to stimulate the temporolimbic regions in such panic disorder patients who were not experiencing an attack elicited increases in EEG delta (slow wave, 2-4 Hz) activity not seen in panic patients without the derealization symptom or in normals (53). In other words, panic patients with temporolimbic symptoms of derealization and other sensory distortions show epileptiform EEG alterations with ambulatory monitoring and/or odor inhalation. By analogy, odor-elicited temporal lobe dysfunction could explain in part the derealization symptom in MCS patients. However, such odor reactivity may be present only under conditions of sensitization, not necessarily in a single, isolated test (28).
Time-dependent Sensitization
Animal studies have permitted systematic examination of the phenomenology and mechanisms of time-dependent sensitization (TDS). Among various efferents, the amygdala sends excitatory input to the nucleus accumbens of the dopaminergic mesolimbic pathway (54). As a result, the amygdala can modulate (but is not necessarily required for) another nonkindling type of neural sensitization known as time-dependent sensitization (55). TDS is the progressive increase in responsivity of a given outcome measure with the passage of time between the initial and later exposures to a pharmacological or nonpharmacological stimulus or stressor (56). Agents that differ widely in their structural and pharmacological properties can all induce, elicit, and/or modulate TDS (56-60), including stimulants, opioids, glucocorticoids, tranquilizers, antidepressants, immunosuppressants, pertussis or cholera toxins, and neuromodulators such as substance P, and volatile organic agents such as ethanol (61), toluene (62), or formaldehyde (63). Sensitizable outcomes may be behavioral, neurochemical, immune, or endocrine. Outcomes may also be bidirectional (increases or decreases), depending on the individual's past history with the sensitizing or cross-sensitizing agent (61,64). Convulsions are not necessarily involved in TDS, and drugs such as anticonvulsants that block kindling do not prevent TDS-type effects (65).
Previous research suggests that the patterns of response to exposures under different time factors can distinguish sensitization from other neurobehavioral processes such as classical conditioning or habituation (Table 1). For example, the initial response to a given stimulus may be of magnitude 1+ in sensitization and habituation. The magnitude of the initial response to a conditioned stimulus (CS) would be 0 in conditioning. Namely, only the unconditioned stimulus (UCS) can elicit the 1+ biological response, and the UCS would not be retested; the initial response to the unconditioned stimulus that is paired with the UCS is 0. Thus, the response magnitude upon initiation could distinguish conditioning from sensitization and habituation. However, if the stimulus is given again soon after the initial exposure, the response is dampened to 0 in habituation, while it remains 1+ in sensitization and grows from 0 to 1+ to the CS in conditioning. Thus, rapid repetition of a stimulus could distinguish habituation from the other two phenomena. After the passage of time, the magnitude of the response in sensitization (amplification of responsivity by passage of time) would be 3+, whereas it would be 1+ in habituation (restoration of responsivity by passage of time without reexposures). In contrast, the magnitude of the response to the CS in conditioning would diminish because of a lack of repeated pairings with the UCS or even oppose that of the UCS (66). Thus, delay between reexposures to a stimulus could distinguish sensitization from the other two phenomena.

Sensitization is further complicated by the potential for interaction with conditioning processes in a context-dependent manner (Table 2). That is, if the initiating and eliciting stimuli are given in the same physical environment, then it is possible to elicit the sensitized response only in that same, familiar environment (35,67). Testing for elicitation of sensitization in an environment different from the one where the process was initiated, (e.g., testing in a laboratory when the illness is reported at work) will elicit only a baseline magnitude of response. In this circumstance, the sensitization may still be present, but not observable. By analogy, the degree of novelty of environments, in ascending order would be home, work, MCS laboratory (Table 2). In context-dependent sensitization, it is preferable to both initiate and elicit sensitization in the laboratory; otherwise, testing in a novel site after initiation in a familiar setting (4) could fail to elicit sensitization when it is actually present.

These context-related concepts derive from previous animal research. Badiani et al. (67) studied the interaction of stimulant drugs with the environment (home versus novel cage for both initiating and test exposures) and with individual differences in behavior over a 1-week protocol. They found that it was possible to induce a greater degree of sensitization of rotational behavior if both initiating and test exposures were given in a novel cage, rather than if the exposures were all given in the home cage. This design parallels previous human studies in which investigators gave the sensitizing exposures (session a) and test exposures (session b) in the same novel laboratory setting (49,50,68). Badiani et al. (67) also demonstrated that the animals with lower responses to amphetamine during the first session exhibited the greater sensitization of rotational behavior after 7 days when sensitizing and test doses were given in a novel environment. In contrast, animals with higher responses to amphetamine during session a exhibited habituation, not sensitization, of rotational behavior after 7 days when all sensitizing and test doses were given in the home environment. Similarly, Sorg et al. (63) noted differential sensitization to formaldehyde as a function of initial locomotor responsivity to a novel environment.
Sensitization is not merely a type of conditioning. Animal studies have demonstrated the ability to extinguish the conditioned responsivity to the experimental context by giving sham exposures (e.g., saline injections) without eliminating the sensitized response to the actual substance (e.g., a drug) in the same setting (69). Re-exposure to the original stimulus immediately elicits the sensitized response despite extinction of the context responsivity. It is also possible to initiate and elicit sensitization in a context-independent manner (70). For this type of sensitization, the environment in which the initiating stimulus is given varies among exposures; whenever the stimulus is readminstered, the later responses will be amplified, i.e., sensitized, regardless of the environment in which the reexposures occur. One animal study suggests that animals with the greatest behavioral reactivity to novelty are more prone to develop both stimulant drug self-administration (71) and context-dependent rather than context-independent sensitization. These findings raise the possibility of studying analogous individual differences in human subjects to explain why one person progresses into severe MCS and another does not.
A sensitization model also accomodates possible comorbid psychiatric disorders and stress factors in MCS. TDS is a neurobiological process, but drugs and stress (physical or psychological) can cross-sensitize (initiate TDS) when tested later in time (56,72,73). Hormones present in the physiological stress response (compare with glucocorticoids) may be required for initiation of TDS to stress (74), though not necessarily to pharmacologic agents (75). Estrogens favor acceleration of the development of TDS in animals (76), and females sensitize more readily than do males (77). TDS is emerging as a leading model for various chronic recurrent disorders such as drug craving and addiction (78), posttraumatic stress disorder (79), bipolar disorder (80), recurrent unipolar depression (80), and eating disorders such as bulimia (56). Various investigators have linked MCS with all of these disorders with the notable exception of drug abuse (81). Antelman (57) and Bell (28,81) have reviewed the extensive overlaps between MCS and TDS. Bell et al. have found increased histories of drug problems in the families of chemically intolerant young adults (48) and of alcohol problems in the families of chemically intolerant middle-aged adults (50). Thus, the genetic vulnerability to substance abuse problems may be present, but may not be expressed as such in MCS patients.
Another leading MCS symptom is concentration difficulty (4,15). This symptom may have neurophysiological correlates in the slow EEG frequency, absolute theta (4-8 Hz). That is, normal young adults trained to produce increased amounts of EEG theta perform more poorly on tests of vigilance than do controls trained to produce decreased amounts of theta (82). We have studied temporoparietal theta activity among young adults with depressed affect by using nasal inhalation of filtered room air immediately following a series of low- level chemical exposures (n-butanol, galaxolide, propylene glycol) and other tasks. Under those conditions, we found increased theta at rest after the chemicals within the chemically intolerant subset compared with those who reported tolerating chemicals (83). Notably, children with attention-deficit/hyperactivity disorder (ADHD) also exhibit increased levels of EEG theta activity, especially during cognitive tasks (84,85), which researchers have linked with feelings of unreality (84). In a recent survey, chemically intolerant young men reported an increased rate of childhood ADHD diagnoses (86). The dopaminergic pathways involved in TDS have also been implicated in ADHD (87).
Bell et al. also have evidence for TDS of the endogenous opioid, plasma -endorphin (2), and of cardiovascular measures (88) over multiple laboratory sessions involving foods and stress in older adults with moderate levels of chemical odor intolerance. The endorphin levels of the chemically intolerant subjects were generally elevated, but changed direction from session to session relative to those of the normals. In addition, greater initial psychological distress correlated with lower endorphin levels later in the study for the chemically intolerant as contrasted with higher endorphin levels under the same conditions for the normals (2). The chemically intolerant group also had waking diastolic blood pressures that were higher on the second than on the first days in the laboratory, whereas the normals showed the opposite pattern (88). Despite this variability, averaged over six measurements, waking blood pressures of the chemically intolerant elderly were higher overall than those of their normal peers. Bell et al. have found increased diastolic blood pressures and/or heart rate over time in two subsequent laboratory studies of chemically intolerant individuals in which chemical exposures were given (49,50). Together, the data suggest instability of certain physiological variables between measurements and paradoxical reversals in the direction of some stress-related responses for chemically intolerant individuals over time. The findings are consistent with Antelman et al.'s (61,64) data on bidirectionality in TDS. Higher peripheral endorphin levels could lead to nonimmunological release of histamine from mast cells (89). If so, endorphin could account for some of the allergylike symptoms such as rhinitis, breathing problems, or hives reported in MCS patients without atopy (3,4,90). Moreover, opioids such as -endorphin can initiate TDS in animal studies (58) and can modulate cardiovascular tone in human subjects (91).
The same group of chemically intolerant elderly described above also exhibited objective polysomnographic sleep patterns such as decreased total sleep time, increased waking, and decreased rapid-eye movement sleep, despite only slightly elevated subjective ratings of sleep disturbance compared with chemically tolerant controls (92). Milk, a commonly implicated food incitant in MCS (4), was associated with poorer sleep than was soy beverage in the chemically intolerant group. One of several possible neurochemical bases for the aroused sleep pattern that would be consistent with TDS is increased dopamine activity and/or responsivity (DA) (93), e.g., in mesolimbic pathways (94). Many but not all animal studies of TDS have reported progressive increases in mesolimbic DA activity during induction of TDS (54,59). DA is also a major neurotransmitter in the olfactory bulb for odor discrimination (94) and in the hypothalamus for inhibition of the reproductive/stress hormone prolactin (95).
Plasma prolactin levels are accessible indicators of CNS dopamine (95,96). That is, increased hypothalamic dopamine has been shown to act as prolactin inhibitory factor, i.e., decreasing prolactin output into the blood. Prolactin is often elevated in cases of psychological or physiological stress (97). Consequently, serum prolactin could offer an objective correlate of sensitization and of stress responses. As part of a study of subsequent blood pressure sensitization (49), Bell et al. examined baseline 4 p.m. resting serum prolactin levels (drawn upon study enrollment and assayed with a standard commercial kit) in middle-aged women with and without self-rated chemical odor intolerance. Data from the depressed and nondepressed controls without chemical intolerance were averaged in this analysis; the resulting two groups (CI and non-CI) did not differ in mean levels of psychological distress (SCL-90-R Global Severity Index, p=0.969). Sitting and standing blood pressures were then taken without concomitant chemical exposures at the beginning and end of two sessions, spaced one week apart. During each session, blinded, placebo-controlled chemical exposures were given, using identical procedures. Significantly more of the chemically intolerant women (8/10, 80%) exhibited increased sitting diastolic blood pressure from week one to week two than did the chemically tolerant women (4/17, 24%) (Fisher's Exact Test, p=0.007). Furthermore, the chemically intolerant women who showed laboratory evidence of blood pressure sensitization had lower baseline prolactin levels, in contrast with chemically tolerant women who did not sensitize blood pressure (when a single hyperprolactinemic outlier was removed) (serum prolactin--CI: 7.8, SD 2.9; non-CI: 11.9, SD 4.1, F(1,19)=6.1, p=0.024). While these observations are preliminary, the lower prolactin level suggests either: increased baseline CNS dopamine activity in the hypothalamus; or decreased CNS hypothalamic dopamine with heightened DA receptor sensitivity in the pituitary of the chemically intolerant individuals. The direction of the group difference for prolactin levels is consistent with sensitization of dopaminergic activity to a low-level initiating stimulus (61), rather than sensitization to a simple stress response model for chemical intolerance (in which more stress should lead to higher prolactin).

Re: CFS, MCS, LGS, & SR. WOW !

Posted by Cont on March 15, 1999 at 22:06:08:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by BELL- neurogenic sensitization on March 15, 1999 at 21:58:28:

However, in view of the variability of the -endorphin data and one prolactin outlier, it will be essential to replicate and extend the blood studies to multiple measurements over different days and different times of day, at rest, and after chemical exposures, in larger samples of subjects. Nonetheless, the data overall suggest a labile but generally activated neurochemical internal milieu in chemically intolerant individuals that may involve at least opioids and dopamine.
Design Implications of Time-dependent Sensitization
Sensitizable and Previously Sensitized IndividualsFor present purposes, hypotheses that derive from a TDS model have major design implications for future studies of exposure-related symptoms in MCS (81). First, an important hypothesis is that a subset of MCS patients may be highly sensitizable individuals, not only to environmental chemicals, but also to foods, drugs, other environmental factors, and life stressors (2,21,27,81,88,98). This implies that environmental chemicals may be the initiating stimulus for the sensitizing process and that chemicals may act synergistically with other classes of stimuli to initiate MCS (21,73). For example, it may be difficult retrospectively to distinguish the sensitizing physiological effects of an acute toxic chemical spill of a single agent from the sensitizing psychophysiological effects of the associated stress response (e.g., -endorphin, cortisol) (99). It may still be possible to try prospective pharmacological agents (e.g., dopamine antagonists to block certain types of TDS initiation) (35,59) or nonpharmacological interventions (e.g., brief cognitive psychotherapy to minimize the perceived stressfulness of the event) at the time of emergency treatment in patients exposed to a chemical spill, to determine if a given class of intervention might prevent the later development of MCS on a TDS basis.
In the laboratory, cross-sensitization between pharmacologic and nonpharmacologic stimuli in TDS means that demonstrating current reactivity to psychological stressors such as placebo will not prove a lack of reactivity to chemical stimuli, and vice versa. The initial question then becomes whether certain MCS patients are sensitized to multiple environmental factors (98), rather than the dualistic question of a toxogenic versus psychogenic etiology for MCS (100). It is also possible that different subsets of MCS patients experience different types of initiation factors, i.e., some may have had early life psychological or physical trauma without chemicals (21,49) whereas others may have undergone only an identifiable chemical exposure event in mid-adulthood (12). Some chemical exposure events such as a toxic spill could invoke both stress and chemical effects to initiate TDS, perhaps via the physiological stress response pathways (72-75). Chemical and stress responses may be dependent on some of the same final common biological mechanisms for initiation or elicitation of sensitization (72,73). A key factor in TDS may be the experienced or perceived threat to the individual from the environment (101,102). Studies must be designed to manipulate systematically not only chemical exposure levels and awareness of chemicals, but also the perceived stressfulness of the setting in which the chemical exposures occur (67,102).
Animal studies suggest that between- group (different groups receiving the active and sham treatments) rather than within-group/crossover (the same groups receiving the active and sham treatments in counterbalanced order) designs may be optimal to differentiate the chemical effects from those of experimental stress (56,69,71,101,102). The difficulty for within-subjects designs is that the sensitizing effects of either an active or a sham exposure may change the subsequent responsivity to the next test (sham or active) in the same individual (56,61,64). For example, Badiani et al. (67) found a much less intense but nonetheless increased response to saline injections in animals that had been pretreated with active stimulant drug in a novel environment, when sensitizing and the test drug doses were all given in a novel environment. However, the saline effect was apparently conditioned to specific circumstances. It was not present for saline when the pretreatment had involved active drug in a home environment, or saline in either home or novel environment. These latter observations may affect the interpretation of studies such as those of Staudenmayer et al. (103), who reported an unreliable pattern of MCS patient symptom data in differentiating chemical from sham challenges. The within-subjects design and the pretesting of masking odors to determine initial lack of reactivity in that study may have initiated a sensitization process to the testing procedures or the masking odors in the MCS patients. Consequently, subjects could have been reactive in a seemingly unreliable manner to various test exposures when they were in fact sensitized to both active and sham agents. This point is important because of recent findings that mint odor, for instance, used repeatedly as a masking odor in Staudenmayer's human MCS study (103), can initiate olfactory-limbic sensitization in animals (34). Similarly, examination of the study designs of nonatopic adverse food reactions in MCS patients suggests that a failure to appreciate the implications of sensitization can lead to widely divergent experimental outcomes (15,26). Systematic designs to test for sensitization with awareness of its potential interactions with contextual conditioning and with adaptation are essential to avoid methodological pitfalls in future MCS chemical and sham exposure studies.
Context-dependent and Context-independent Sensitization
Second, as discussed above, TDS can develop in either context-dependent (conditioned) or context-independent ways (35,55,59,67,102). That is, varying the setting in which the sensitizing substance is encountered will enable the individual to exhibit a sensitized response in any setting (context-independence). However, if the chemical exposure is usually paired with particular environmental, nonchemical cues (context-dependence), then single session studies in a novel laboratory situation may miss a true effect. Studies have shown that animals with established sensitization who receive the test agent in a new cage different from the one in which the drug was usually given during initiation of sensitization will not show a sensitized response. When returned to the original, drug-paired setting, sensitized animals will again exhibit heightened responsivity to the drug (35) (Table 2). Furthermore, in established context-dependent TDS, environmental chemicals may not be the only eliciting stimulus for symptoms. Some degree of heightened response may occur in animals given saline in the cage previously paired with active drug (67). Consequently, the inherent stressfulness, familiarity, or novelty of the experimental setting and procedures themselves may play a substantial role in the outcome of MCS studies involving TDS (35,67,69,71,75,104). Both context-dependent and context-independent sensitization theoretically might occur in the same person. However, animals prone to drug self-administration (71) may be particularly susceptible to the context-dependent form; whereas animals not prone to stimulant drug self-administration (compare with a large subset of MCS patients) (63) may be particularly susceptible to the context-independent form (71).
This argument implies that field studies in familiar settings such as office, factory, shopping malls, car, and home environments may be as important as laboratory studies. In this manner, it may be possible to detect sensitized responses to chemicals that would be obscured in acute tests within a novel and often threatening laboratory setting. However, multiple test sessions over periods of days and weeks in the same setting would also help avoid type II error by facilitating development and elicitation of context-dependent sensitization to the experimental procedures (67), even if the ability to elicit pre-existing sensitization were initially inhibited (35).
It is also possible to design studies to differentiate conditioned from sensitized response. For example, Stewart's group (69) extinguished the conditioned component of a heightened response with saline injections by repeated reexposure of the animals to the previously drug-paired environment until the size of the response returned to baseline. However, when they gave the drug again, the sensitized response immediately reappeared, suggesting that extinction addressed only the context-dependent part of the process, not the sensitization itself. Certain investigators have claimed the ability to desensitize MCS patients to chemicals by particular psychological extinction procedures (103). It would be crucial to determine not only if the procedures are actually effective in some MCS patients, but also if such extinction eliminates chemical sensitization completely, or simply the conditioned elicitation of adverse reactions in certain situations (69,71). The long-term health implications of remaining sensitized, even though not exhibiting context-dependent sensitized reactions in some settings, are unexamined at this time.
Sensitization and the Adaptation Hypothesis
The sensitization hypothesis is compatible with the MCS-derived adaptation hypothesis; that is, a long-standing precept in MCS is that the heightened reactivity and another process, called masking or adaptation, can develop at the same time (5,10). The corollary hypothesis is that adaptation may obscure the ability to detect sensitized responses during challenge tests (Tables 1, 2). Complete removal from all adaptation-inducing exposures for 4 or more days is required prior to attempting definitive testing for true adverse reactions to chemicals (10). Simple environmental chambers are insufficient, as subjects can remain in them for only a few hours during a day, with little impact on the adaptation process (5,10). The practical and financial limitations of developing environmentally controlled units for research have impeded progress in testing the adaptation hypothesis.
Historically, many neurobiological researchers have noted that sensitization and habituation (compare tolerance, adaptation) are distinct but interactive processes (71,105,106). Post (106) pointed out that continuous or frequent exposures to a given stimulus favor development of tolerance, whereas intermittent exposures favor development of sensitization. Studies have shown that sensitization and habituation are not opposite ends of the same process, but independent, concomitant processes that can summate. Habituation added to an otherwise sensitized response could result in mutual cancellation of effects, i.e., an apparent lack of change over time (105). Moreover, habituation to the test environment itself in an acute test of a substance can interact with individual differences in inclination to drug self-administration to alter drug response (35,67,71). Animal studies indicate that MCS patients (who do not tend to be drug abusers) might not show their capacity for heightened reactivity to a chemical during an initial, one-session test. Thus, the basic neuroscience literature supports the MCS contention that adaptation and cross-adaptation to chronic chemical exposures could obscure evidence of heightened reactivity (Table 1). Days, not hours, of withdrawal from the sensitizing substance are needed to be able to elicit a heightened response in TDS (54,59,71). Individual differences in responses to habituation to the total (chemical, physical, and psychosocial) environment in which the substance is encountered also may alter the outcome of a given chemical challenge (35,71,102,107,108).
Time Factors in Experimental Approaches
Available data indicate two primary ways to design human studies testing for heightened reactivity to environmental chemicals: a) place patients in an environmentally controlled unit and remove them from all sources of the suspect chemicals and cross-sensitizing stimuli for a period of days prior to challenge tests (10). This effectively removes habituation while providing optimal time for emergence of sensitization; b) use inherently more versus less sensitizable individuals and induce context-dependent sensitization to common chemicals in an initially novel laboratory setting over multiple sessions, separated by days from one another (2,68,98). Such a procedure would make the heightened reactivity to an otherwise familiar and habituated substance dependent upon the new setting in which it is encountered (67).
Design a relies largely on deadaptation to reveal pre-existing, context-independent sensitization. It is important to emphasize that both sensitization and habituation are likely to contribute to the reported patterns of reactivity in MCS patients in an environmental control unit (design a). That is, if adaptation to ambient exposures outside the unit were the only issue, then removing adaptation by avoidance for a few days would restore not hyperreactivity, but simply reactivity. Instead, clinicians observed a marked hyperreactivity (10,16), matching that of a sensitized response (35,102).
Design b relies largely on experimentally initiated, context-dependent (conditioned) sensitization. The individual may or may not have had preexisting sensitization to the substance. The underlying assumption is that the patient is inherently more sensitizable than a normal person. Design b takes advantage of the possibility of inducing and then testing for sensitization by using the laboratory setting itself to make the first exposure to the substance novel and the later exposures familiar, i.e., to foster context-dependent sensitization (Table 2). Newlin and Thomson (68) have already demonstrated the feasibility of design b in human subjects. They compared changes in autonomic nervous system responses to ingestion of alcohol on three different days in sons of alcoholics and sons of nonalcoholics (all of whom used alcohol socially and nonabusively). The outpatient sessions were spread over a two-week period in the National Institute of Drug Abuse laboratory. The sons of alcoholics exhibited less ability to habituate and more capacity to sensitize the autonomic measures over sessions than did the control subjects. They also tested for conditioned responses to the laboratory setting alone, without alcohol after the last session. Autonomic patterns reverted to baseline levels in the absence of alcohol. Thus, a context-dependent sensitization to alcohol was observed in sons of alcoholics, in which the conditioned component relied on concomitant exposure to the substance and to the setting, not to the setting alone.
Our own preliminary polysomnographic, quantitative EEG, endorphin, and cardiovascular data suggest the feasibility of the multiple, identical-session design for MCS studies. This approach may permit induction and elicitation of sensitized responding in chemically intolerant human subjects without necessitating use of an environmentally controlled hospital unit. However, designs a and b facilitate asking different types of questions. For design a, the main question can be whether the individual is currently sensitive to a given substance. For design b, the main question can be whether the individual is unusually sensitizable.
Another important methodological consideration is that exposure levels must be intermittent and perhaps fluctuating, with breaks of hours and even days from one exposure to the next, if sensitization is to develop (106). The constant levels of chemicals used in many toxicology studies could minimize sensitization and favor tolerance. Real-world exposures in human populations are generally intermittent and fluctuate over time. Previous investigators have treated inconsistencies in dose during laboratory studies as a potential procedural flaw. On the contrary, the constancy and lack of interruptions in experimental dosing may help explain why tolerance has been reported more often than sensitization in toxicology research., The major ethical consideration for this research in humans is the need to limit the number of repeated exposures during the research protocol. Kalivas et al. (59) point out that sensitization to a few scattered exposures is temporary and reversible, but massed daily exposures for a week induce permanent sensitization in animals.
MCS is much more than behavioral avoidance of chemicals; explanations of MCS must account for a broad range of clinical observations (100). These observations include low rates of drug use and abuse despite elevated levels of affective distress (28). The partial limbic kindling and TDS model has a limited, but growing, amount of empirical evidence in humans (2,27,88,109) and in animals (34,44,45,62,63) to support its involvement in the multiple symptoms, phenomenology, and medical/psychiatric pictures of MCS patients (81). In particular, the sensitization model suggests specific experimental design considerations, without which one risks missing a true effect (type II error). Previous hypotheses for MCS involving sensitization, conditioning, and adaptation have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena (35,59,67,69,71,105,106).

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Re: CFS, MCS, LGS, & SR. WOW !

Posted by references on March 15, 1999 at 22:07:10:

In Reply to: Re: CFS, MCS, LGS, & SR. WOW ! posted by Cont on March 15, 1999 at 22:06:08:

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Just a personal response to Mike

Posted by Johnelle on March 15, 1999 at 22:19:56:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

JN has a lot to say OBVIOUSLY, but I just want to reassure
you that you are on the right track and I admire your
hanging around here and reading Dr. Stoll's book and
beginning the SR, etc.

I can remember having such problems with MCS that when my
husband would put on his cologne I could immediately TASTE
it! My feeling is that you will know you're healing your
gut when you lose your MCS. There is a test for LGS that
can be done through SOME doctors. Most haven't a clue
though. It is a relatively simple urine specimen kit you
take home and do over about a 10-hour period, and you send
in your specimens to Great Smokies Diagnostic Lab, 63
Zillicoa Ave., Asheville, NC 28801.

I was diagnosed with FMS about two years ago and began SR
about six months ago. I had a coaching session over the
phone with Dr. Stoll which was immensely helpful. He said
after I had been practicing SR for 2 weeks or more to find a
biofeedback therapist who could test me, just to tell them,
"I am practicing skilled relaxations and want to be tested
to see if I am reaching the relaxation response." If they
don't know what you're talking about, or they want you to
come in for an eval or a series of sessions, just hang up,
Dr. Stoll said. I had difficulty locating a bio therapist,
but finally found someone, and I was not reaching the slower
brainwave patterns that I was supposed to, so after bouncing
it off Dr. Stoll, I had a series of six sessions with her to
retrain the brain. I also bought a sound and light
entrainment device from her which cost $349, and it does
what she did with me the six sessions. The various programs
start in sync with your own brain frequencies and then
descend to help you get slowed down (in my case anyway). I
love that thing and wouldn't leave home without it :o)

If you want to read about it or order one, I bought it from
They also have several cassettes to aid in SR. This website
belongs to my biofeedback therapist and her psychologist
husband in Houston, TX.
Hope this helps, and your wise choices serve to strengthen
us all by reassuring us we're all in this t

Re: Just a personal response to Mike

Posted by Toxicant loss tolerance Miller on March 15, 1999 at 22:25:51:

In Reply to: Just a personal response to Mike posted by Johnelle on March 15, 1999 at 22:19:56:

Toxicant-induced Loss of Tolerance--An Emerging Theory of Disease?
Claudia S. Miller
Department of Family Practice, The University of Texas
Health Science Center, San Antonio, Texas
Features of TILT Relevant for Its Testing
Stimulatory and Withdrawal Symptoms
Testing the TILT Theory
This paper attempts to clarify the nature of chemical sensitivity by proposing a theory of disease that unites the disparate clinical observations associated with the condition. Sensitivity to chemicals appears to be the consequence of a two-step process: loss of tolerance in susceptible persons following exposure to various toxicants, and subsequent triggering of symptoms by extremely small quantities of previously tolerated chemicals, drugs, foods, and food and drug combinations including caffeine and alcohol. Although chemical sensitivity may be the consequence of this process, a term that may more clearly describe the observed process is toxicant-induced loss of tolerance. Features of this yet-to-be-proven mechanism or theory of disease that affect the design of human exposure studies include the stimulatory and withdrawallike nature (resembling addiction) of symptoms reported by patients and masking. Masking, which may blunt or eliminate responses to chemical challenges, appears to have several components: apposition, which is the overlapping of the effects of closely timed exposures, acclimatization or habituation, and addiction. A number of human challenge studies in this area have concluded that there is no physiological basis for chemical sensitivity. However, these studies have failed to address the role of masking. To ensure reliable and reproducible responses to challenges, future studies in which subjects are evaluated in an environmental medical unit, a hospital-based facility in which background chemical exposures are reduced to the lowest levels practicable, may be necessary. A set of postulates is offered to determine whether there is a causal relationship between low-level chemical exposures and symptoms using an environmental medical unit. -- Environ Health Perspect 105(Suppl 2):445453 (1997)
Key words: adaptation, chemical sensitivity, masking, multiple chemical sensitivity, sensitivity, sensitization, tolerance, addiction, habituation
This paper is based on a presentation at the Conference on Experimental Approaches to Chemical Sensitivity held 2022 September 1995 in Princeton, New Jersey. Manuscript received at EHP 6 March 1996; manuscript accepted 9 September 1996.
Research for this paper was supported in part by an appointment to the Agency for Toxic Substances and Disease Registry (ATSDR) Clinical Fellowship Program in Environmental Medicine, administered by Oak Ridge Associated Universities through an interagency agreement between the U.S. Department of Energy and ATSDR.
Address correspondence to Dr. C.S. Miller, Department of Family Practice, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7794. Telephone: (210) 567-4557. Fax: (210) 567-4579. E-mail: millercs@uthscsa.edu
Abbreviations used: EMU, environmental medical unit; TILT, toxicant-induced loss of tolerance.
Clinical observations in North America (17) and Europe (8) point to an expanding group of patients who report sensitivities to extraordinarily low levels of environmental chemicals. This phenomenon, termed chemical sensitivity or multiple chemical sensitivity, appears to develop de novo in some individuals following acute or chronic exposure to a wide variety of environmental agents including various pesticides, solvents, drugs, and air contaminants in so-called sick buildings. Some practitioners have attributed a broad spectrum of chronic medical conditions involving any and every organ system to chemical sensitivity (Figure 1) (4).
Figure 1. Some conditions that have been attributed to chemical sensitivity.
Efforts to formulate a case definition for chemical sensitivity, to identify relevant biomarkers, and to explore a variety of mechanisms for the condition have escalated over the past decade. Several conflicting schools of thought have evolved with respect to underlying mechanisms, ranging from the purely psychological to the wholly physiological. In the midst of the tumult surrounding chemical sensitivity lies a profound but little-recognized scientific debate concerning the origins of disease. Some participants in this debate are challenging currently accepted notions concerning the causes for many chronic illnesses.
This paper attempts to clarify the nature of chemical sensitivity by describing a general mechanism that appears to underlie these cases; proposes a theory of disease based upon this general mechanism; and offers a set of testable postulates for corroborating or refuting this theory. Science is not about opinion or belief; it is about "guess and test," that is, formulating hypotheses and then devising experiments to test them.
Phenomenologically, chemical sensitivity appears to develop in two stages (3,4). First is the loss of tolerance (possibly but not necessarily due to sensitization) following acute or chronic exposure to various environmental agents such as pesticides, solvents, or contaminated air in a sick building. Second is the subsequent triggering of symptoms by extremely small quantities of previously tolerated chemicals, drugs, foods, and food and drug combinations (Figure 2). Although sensitivity to chemicals may be one of the consequences of this two-stage process, the term chemical sensitivity does not appropriately describe the process involved.

Figure 2. Phenomenology of chemical sensitivity. Chemical sensitivity appears to develop in two stages: Stage 1--loss of specific tolerance following acute or chronic exposure to various environmental agents such as pesticides, solvents, or contaminated air in a sick building; and Stage 2--subsequent triggering of symptoms by extremely small quantities of previously tolerated chemicals, drugs, foods, and food and drug combinations (e.g., traffic exhaust, fragrances, caffeine, alcohol). Physicians formulate a diagnosis based on symptoms reported to them by their patients. Because of masking, both physicians and patients may fail to observe that everyday low-level exposures are triggering symptoms. Sometimes even when such triggers are recognized, an initial exposure event that initiated loss of specific tolerance may go unnoticed or may not be linked by the physician or the patient to the patient's illness.

There are two principal reasons for this. First, although chemical sensitivity certainly sounds like an inconvenient problem to have, the words fail to convey the potentially disabling nature of the condition and its postulated origins in a toxic exposure. Some researchers balk at using the word toxic in this manner. However, numerous investigators from different geographic regions have published strikingly similar descriptions of individuals who report disabling illnesses after exposure to recognized environmental contaminants, albeit at levels not generally regarded as toxic (1,912). Yet, for these individuals, the exposure appears to have been toxic.
Paracelsus aptly opined that dose makes the poison. However, as our knowledge has grown, it has become evident that dose + host makes the poison (for example, pack-years of smoking plus *-1-antitrypsin deficiency). Similarly, in the case of chemical sensitivity, not everyone exposed in a sick building or to a chemical spill develops chronic illness. Thus, it may be concluded that individual susceptibility, whether physiological or psychological, must play a role in determining who gets sick. The term chemical sensitivity fails to convey this key observation that chemical exposures appear to initiate a process that results in chemical sensitivity. Conceivably, this phenomenon could represent a new type of toxicity.
The second problem with the term chemical sensitivity is that it suggests that those afflicted become intolerant of chemical exposures only when, in fact, caffeine, alcoholic beverages, various drugs, and foods reportedly trigger symptoms in these individuals once the process has been initiated (4,1215). For the above reasons, chemical sensitivity is a misnomer for the process under discussion. An alternative term, toxicant-induced loss of tolerance (TILT), has been proposed (16). This term offers several advantages. First, it describes the process as it has been observed by clinicians and patients. Second, it allows for the possibility that various toxicants may initiate the process. Third, it does not limit the resulting intolerance to chemicals. Finally, it sharpens the focus of the current debate over chemical sensitivity by positing a theory of disease that can be subjected to objective testing.
Historically, new theories of disease arose when physicians observed patterns of illness that did not fit accepted explanations for disease at that time, for example, the germ theory or the immune theory of disease. Similarly, many of the illnesses under discussion here do not conform to current accepted explanations for disease or toxicity. Objections to the concept of chemical sensitivity have included concerns that: too many different chemicals have been said to cause chemical sensitivity; patients report too many symptoms involving any and every organ system; no known physiological mechanism explains chemical sensitivity; no biomarker has been identified for chemical sensitivity; and total avoidance of chemicals is impractical.
Theories of disease attempt to explain what is going on inside the patient (a "black box") before overt illness, as illustrated below:

A theory of disease is a yet-to-be-established, general mechanism for a class or family of diseases. For the germ theory of disease, the boxes depicting the general mechanism of infection would look something like this:

Note that: many different kinds of germs cause responses; there are many different responses involving any and every organ system (skin, respiratory, gastrointestinal); specific mechanisms vary greatly--for example, cholera versus AIDS versus shingles; there is no single biomarker--identification of specific germs took years; and prevention (avoidance, antiseptics, sanitation, use of gloves) preceded knowledge of specific mechanisms.
For the immune theory of disease, the boxes might look like this:

Here, just as for the germ theory of disease: many different kinds of antigens cause responses; there are many different responses involving any and every organ system (skin, respiratory, gastrointestinal); specific mechanisms vary greatly--for example, poison ivy versus allergic rhinitis versus serum sickness; there is no single biomarker--identification of specific antibodies took years; and prevention (avoidance, allergy shots) preceded knowledge of specific mechanisms.
For toxicant-induced loss of tolerance, the boxes might look like this:

For toxicant-induced loss of tolerance, as for the germ and immune theories of disease: many different kinds of chemicals may cause responses; there may be many different responses involving any and every organ system; specific mechanisms may vary greatly; it is conceivable that there is no single biomarker for response--identification of biomarkers may take years; and prevention (avoidance of initiators or triggers) may precede knowledge of specific mechanisms.
Although the concept loss of tolerance may sound vague, in fact it is not. What these individuals report is a loss of specific tolerance to particular chemicals, foods, and drugs. (16). Note that this theory does not exclude the possibility that toxicant-induced loss of tolerance could turn out to be a special kind of toxicity or a variation on the immune theory of disease just as allergy and delayed-type hypersensitivity are special cases that fall under the general classification of immunologic disorders. A consequence of viewing TILT as a theory of disease would be a shift in perspective from chemical sensitivity as a syndrome to chemical sensitivity, now TILT, as a class of disorders parallel to infectious diseases or immunologic diseases. Much effort has been devoted to developing a case definition for chemical sensitivity, with a singular lack of success. This lack of success would not be surprising if in fact TILT represented a new class or family of disorders. Certainly, it would not be feasible to develop a single clinical case definition that would embrace all infectious or all immunologic diseases.
Theories of disease that withstand scientific scrutiny arise infrequently. The past century has witnessed the inculcation of the germ and immune theories of disease into medical practice. Equating toxicant-induced loss of tolerance to either one of these theories, both of which have been widely corroborated, would be premature and presumptuous. On the other hand, toxicant-induced loss of tolerance has certain earmarks of an emerging theory of disease, including the vituperative professional disputes that surround it (16).
Features of TILT Relevant for Its Testing
As described by many investigators, this phenomenon appears to involve a two-stage process. Because of ethical considerations, the first stage (initiation) is more difficult to model in humans than the second stage (triggering). Ultimately, epidemiologic studies and animal models may elucidate the first stage. Fortunately, the second stage readily lends itself to testing via direct human challenges, a potent form of scientific evidence. However, in the design of human challenge studies in this area, certain key clinical observations must be taken into account. First, the commonly reported biphasic, stimulatory-and-withdrawallike pattern of the patients' symptoms, particularly those symptoms involving the central nervous system, must be understood to perform meaningful test challenges on these patients. Second, a related phenomenon called masking (to be described further) may hide responses to low-level chemical challenges and therefore may need to be minimized before testing. Controlling masking may be analogous to controlling background noise in studies on sound.
The following sections will discuss these clinical features, their incorporation in experimental designs, and how failure to do so might threaten research outcomes.
Stimulatory and Withdrawal Symptoms
Randolph first described the time course of the responses of these individuals to chemicals and foods (17). He reported striking parallels between their symptoms and those associated with alcohol and drug addiction. Randolph viewed the food and caffeine addictions his patients exhibited as the bottom rungs in a hierarchy of addiction, proceeding from foods and food and drug combinations such as caffeine and alcohol on the lower rungs upward to nicotine and other naturally occurring and synthetically derived drugs (14).
Chemically sensitive patients resemble drug addicts in that members of both groups often report intense cravings and debilitating withdrawal symptoms. However, chemically sensitive patients' responses are not primarily to drugs. These individuals more commonly report addictions to caffeine or certain foods. While drug addicts manifest ad-dicted behaviors (Latin ad "toward" + dicare "proclaim"), chemically sensitive patients respond as though they were ab-dicted (Latin ab "away from" + dicare "proclaim") and assiduously avoid the very substances addicted persons favor including alcohol, drugs and nicotine.
The stimulatory and withdrawal symptoms reported by chemically sensitive patients are frequently identical to those reported by normal persons exposed to much greater amounts of the same substances. For example, after drinking one cup of coffee, chemically sensitive patients may report feeling hyperactive, jittery, talkative, nervous, anxious, or experiencing paniclike symptoms (stimulatory phase). Hours to days later, they may report withdrawal symptoms such as fatigue, yawning, confusion, indecisiveness, irritability, depression, loss of motivation, blurred vision, headaches, flulike symptoms, hot or cold spells, or heaviness in their arms and legs (withdrawal phase). Similar symptoms occur during caffeine withdrawal among some low-to-moderate caffeine users in the general population (18). Large numbers of chemically sensitive patients and many Gulf War veterans with unexplained illnesses report that one drink of an alcoholic beverage causes inebriation and/or a severe hangover (12,15,19). These augmented responses suggest that those afflicted have lost their previous natural or native tolerance for such exposures.
Early in their illnesses, before eliminating caffeine from their diets, many chemically sensitive patients report having consumed chocolate, coffee, tea, or cola addictively, often in very large quantities (15). Some carried large containers of coffee or tea around wherever they went. Many report later stopping use of all caffeine and xanthines, generally on the advice of a friend or physician, and subsequently experiencing several days of intense withdrawal symptoms. Frequently they report that it was only after eliminating all xanthines from their diets that they were able to discern the effects of consuming a single cup of coffee or a chocolate bar. Most report becoming aware of the unpleasant effects of caffeine only after a trial of partial or complete caffeine avoidance. In this regard, chemically sensitive patients resemble certain reformed smokers or alcoholics who after quitting their addictants report extreme sensitivity to minute amounts of the addicting agents. Terms like addiction, withdrawal, and detox pepper the vocabulary of chemically sensitive patients. One patient described the condition as being "like drug abuse without any of the fun." These parallels to addiction provide perspective: they may help explain why the mechanisms that underlie chemical sensitivity have been difficult to define and why biological markers have proven elusive.

In summary, drug addiction and TILT share a number of features in common. TILT also has features reminiscent of toxicity and allergy (Table 1). However, it is its resemblance to addiction that is perhaps most striking and that has escaped the attention of many physicians and researchers.
Suppose that TILT was a mechanism underlying certain cases of chronic fatigue, migraine, asthma, or depression. It might be reasonable to wonder, then, why patients experiencing these symptoms do not also report chemical intolerances. In fact, some but not all patients do report them (21,22). Many chemically sensitive patients with these same diagnoses report that it was not until they accidentally or intentionally avoided a sufficient number of their problem incitants that they noticed feeling better. Then, when they reencountered one of those incitants, robust symptoms occurred. As they repeated this iterative process of avoidance and reexposure, they noticed that particular symptoms occurred with particular exposures. Most indicate that had they not avoided many chemicals and foods simultaneously, or unmasked themselves, they might not have determined what was making them sick.
Masking and unmasking are colorful lay terms for which there is no scientific equivalent. Nevertheless, investigators' abilities to understand masking and unmasking and manipulate these variables knowledgeably may determine the success of studies in this area. When chemically sensitive patients follow a diet free of their problem foods and live in a relatively chemical-free home in the hills of central Texas where there are no major agricultural or industrial operations or air contaminants, they say they are in an unmasked state. Under these circumstances they claim that if a diesel truck drove by they could identify specific symptoms due to the diesel exhaust, for example, irritability, headache, or nausea.
On the other hand, the patients report that when they travel to a large city like Houston or New York City, stay in a hotel room, and eat in restaurants, they become masked. In the presence of many concurrent exposures (exhaust, fragrances, volatiles offgassing from building interiors, various foods) in New York City many report feeling chronically ill, as if they had flu. If a diesel truck drove by under these circumstances, most report they would not be able to attribute any particular symptoms to the exhaust because of background noise from overlapping symptoms occurring as a consequence of overlapping or successive exposures. In theory, such background noise or masking hides the effects of individual exposures--responses are blurred.
Masking appears to involve at least three interrelated components, any of which may interfere with the outcome of low-level chemical challenges in these individuals: acclimatization, apposition, and addiction. In real life, these three components probably operate concurrently, although here they are considered individually.
There is some notation that can be used to help depict these components. In the addiction literature, responses to addictive drugs are often illustrated graphically using a biphasic curve or sine wave (Figure 3). The portion of the sine wave above the horizontal axis represents symptoms with onset of exposure, often called stimulatory symptoms; the portion below the horizontal axis represents symptoms with offset or cessation of exposure, often referred to as withdrawal symptoms. The height or amplitude of the sine wave in either direction is proportional to the severity of the response. For persons not sensitive to a particular substance, the curve would be a flat line with zero amplitude in either direction. The length of the biphasic curve represents the duration of symptoms following an exposure, reportedly ranging from minutes up to several days depending upon the exposure and the individual. Of course, the particular nature of the symptoms vary from one sensitive subject to the next and from substance to substance.

Figure 3. Graphic representation of symptom progression following exposure to a single substance in a person sensitive to that substance (e.g., caffeine, a solvent, alcohol, nicotine). The portion of the biphasic curve above the line represents symptoms with onset of exposure (stimulatory symptoms) and the portion of the curve below the line represents symptoms with offset of exposure (withdrawal symptoms). Amplitude is proportional to symptom severity. The length of the curve (duration of symptoms) may range from minutes to days.

Suppose researchers wished to test a putatively sensitive subject by exposing him to a low concentration of xylene. Xylene is a common indoor air contaminant and a component of Molhave's mixture (23) that has been used in human inhalation challenge studies. How would the researchers ensure that their subject was unmasked (at true baseline) before challenge? The following components of masking would need to be considered and controlled:
Acclimatization. For most of the population, with continuous or repeated exposure to many environmental stressors, adaptation occurs. That is, symptoms diminish as exposure continues. Chemically sensitive patients' symptoms also decrease with continuing exposure; however, when exposure ceases, these individuals often report marked withdrawal symptoms. Thus, what they describe is more akin to habituation than to adaptation. Suppose further that the subject who is challenged with xylene works in a sick building where he is routinely exposed to low levels of xylene on a regular basis. Administering a test exposure of xylene below the odor threshold (0.62 ppm) (24) may produce little or no effect on the subject if he has been working in that same building during the preceding week (Figure 4). On the other hand, if he avoided the building and all other sources of xylene for 4 to 7 days before testing, a more robust response to the xylene challenge might be anticipated.

Figure 4. Graphic representation of acclimatization. Symptom severity decreases with repeated closely timed exposures (inhalant or ingestant) to the same substance. Acclimatization is not equivalent to adaptation, since patients report withdrawal symptoms after exposures cease; conceptually, acclimatization more closely resembles habituation in this case.
Thus, a sensitive subject's response to a challenge may range widely in intensity, from none to maximal, depending on how recently that person has been exposed to the test substance or a chemically related substance. If insufficient time has elapsed, for example, less than 4 days, the challenge may yield a false negative response as a result of habituation. If too much time has elapsed, for example, weeks or months, sensitivity may have waned.
Apposition . Suppose next that the research subject is sensitive to multiple substances. On the day he is scheduled for challenge testing, he gets up in the morning, uses some scented soap or hair spray, cooks breakfast on a gas stove, and drives his car through heavy traffic to reach the laboratory. Inside the laboratory building he rides an elevator where he is exposed to people wearing various colognes. If he were sensitive to several of these exposures, his responses might overlap in time. Such responses reportedly can last for hours or days. If this is true, they could persist during a placebo challenge, resulting in a false positive response. Thus, apposition or juxtaposition of the effects of closely timed exposures is a second component of masking that must be controlled prior to and during challenge studies (Figure 5).

Figure 5. Graphic representation of apposition. If an individual is sensitive to many different substances, the effects of everyday exposures to chemicals, foods, or drugs may overlap in time. This apposition of effects might lead to an individual who feels ill most of the time; however, neither the individual nor his physician notices the effect of any single exposure. Apposition tends to mask the effect of interest (solid lines) in much the same way that background noise masks a sound of interest.
Addiction . Many of the symptoms reported by chemically sensitive patients mirror those commonly associated with addiction. Addiction may be a component of masking. Addicted individuals consciously or subconsciously time their next "hit" so as to forestall withdrawal symptoms (Figure 6), a phenomenon that occurs in alcohol, tobacco, and caffeine addictions. However, addiction to foods also is reported among chemically sensitive patients. Randolph described wheat, eggs, milk, and corn as the most common addictants in his patients (14,17). Frequently these individuals report intense cravings and consume astounding quantities of foods, for example, a pound of chocolate, several bags of popcorn, a dozen doughnuts, or 30 cups of coffee in one day. Patients most often report this kind of addictive consumption in the early stages of their illness, before they practiced avoiding problem exposures.

Figure 6. Graphic representation of addiction. A sensitive person who is addicted to caffeine, alcohol, nicotine, or another substance may deliberately take that substance at frequent, carefully spaced intervals to avoid unpleasant withdrawal symptoms. Such exposures may also mask the effect of interest (e.g., a challenge test using xylene).
Foods may contain bioactive constituents such as tyramine, monosodium glutamate, and opiates (13). Persons who routinely use tobacco, caffeine, alcohol, or foods containing bioactive substances may need to avoid these substances before testing because the pharmacologic effects of these agents could override or mask the effect of an experimental challenge. Failure to eliminate addictants before testing could result either in false positive challenges due to lingering symptoms from an addictant used in the hours or days preceding a placebo challenge or in false negative challenges due to masking by an addictant.
Testing the TILT Theory
After the germ theory of disease was introduced in the late 1800s, many overly enthusiastic investigators who were careless in their bacteriological techniques announced they had discovered causative agents for tuberculosis, yellow fever, and other diseases. These pronouncements and subsequent retractions became so frequent that in 1884 the President of the New York Academy of Medicine lamented that a bacteriomania had swept over the medical profession (25). To prevent future such pseudodiscoveries, Robert Koch, who identified the organisms responsible for tuberculosis, anthrax, and cholera, proposed a set of rules for etiological verification. His postulates required that: the microbe must present in every case of the disease; it must be isolatable in pure culture; inoculating a healthy animal with the culture must reproduce the disease; and the microbe must be recoverable from the inoculated animal and be able to be grown again.

Figure 7. Graphic representation depicting the testing of the toxicant-induced loss of tolerance postulates using an environmental medical unit. In the left-hand portion of the figure, a chemically sensitive individual is experiencing symptoms in response to multiple exposures (chemicals, foods, drugs) before entering the environmental medical unit. Effects overlap in time. The effect of any particular exposure cannot be distinguished from the effects of other exposures, and the person's symptoms may appear to wax and wane unpredictably over time. Postulate 1--When all chemical, food,and drug incitants are avoided concurrently, remission of symptoms occurs.

Re: Just a personal response to Mike

Posted by cont on March 15, 1999 at 22:29:17:

In Reply to: Re: Just a personal response to Mike posted by Toxicant loss tolerance Miller on March 15, 1999 at 22:25:51:

Figure 7. Graphic representation depicting the testing of the toxicant-induced loss of tolerance postulates using an environmental medical unit. In the left-hand portion of the figure, a chemically sensitive individual is experiencing symptoms in response to multiple exposures (chemicals, foods, drugs) before entering the environmental medical unit. Effects overlap in time. The effect of any particular exposure cannot be distinguished from the effects of other exposures, and the person's symptoms may appear to wax and wane unpredictably over time. Postulate 1--When all chemical, food,and drug incitants are avoided concurrently, remission of symptoms occurs. Anecdotally, patients report going through withdrawal or detox for the first several days during which they experience symptoms such as increased irritability, headaches, and depression. After 4 to 7 days, most report feeling well and theoretically are at a clean baseline. Postulate 2--A specific constellation of symptoms occurs with reintroduction of an incitant. Postulate 3--Symptoms resolve when the incitant is again avoided. Postulate 4--Reexposure to the same incitant within an appropriate window of time (estimated to be about 47 days) produces the same symptoms. For research purposes, challenges should be conducted in a double-blind, placebo-controlled manner.
Just as bacteriomania engulfed the medical profession in the 1880s, chemomania is poised to engulf it now. Chemical sensitivity is in need of a set of postulates to ensure that future causal determinations are scientifically based. Below is a set of postulates that, if met, would confirm (and if not met, refute) that a person's symptoms were caused by a particular substance:
When a subject simultaneously avoids all chemical, food and drug incitants, remission of symptoms occurs (unmasking).

A specific constellation of symptoms occurs with reintroduction of a particular incitant.

Symptoms resolve when the incitant is again avoided.

With reexposure to the same incitant, the same constellation of symptoms reoccurs, provided that the challenge is conducted within an appropriate window of time. Clinical observations suggest that an ideal window is 4 to 7 days after the last exposure to the test incitant.
To apply these postulates (illustrated in Figure 7), the timing of exposures and the degree of masking should be rigorously controlled. To accomplish this, a hospital-based clinical research facility, an EMU, is needed to isolate subjects from background exposures (Figure 8) (4,5,15,16,26). The EMU would be constructed, furnished, and operated to minimize exposure to airborne chemicals. For example, no disinfectants, perfumes, or pesticides would be allowed in the unit. Ventilation would maximize fresh outside air and provide optimal particulate and gas filtration. Patients would eat chemically less-contaminated foods and water, testing one food per meal to determine the effects of specific foods. If symptoms persisted despite this approach, fasting for a few days would be attempted before reintroducing single foods.
The rationale for housing subjects in an environmentally controlled facility for several days before challenges is 2-fold: to prevent extraneous exposure of patients to inhalants or ingestants so responses to them are not misinterpreted as positive responses when placebo challenges are administered (false positives), and to minimize masking that might blunt or eliminate responses to active challenges (false negatives).

Figure 8. Preliminary design sketch of a patient room in an environmental medical unit. Note use of the nonoutgassing construction materials and furnishings and point source control (ventilated television enclosure).
Although the terms exposure chamber and environmental medical unit appear similar, conceptually they differ in important ways with regard to patient safety and control of interfering exposures.
By definition, an EMU is in a hospital where patients can remain 24 hr a day in a clean environment for up to several weeks. Like an intensive care unit or coronary care unit, the EMU would be a specialized, dedicated hospital facility. The EMU must be in a hospital to accommodate very sick patients; exposure chambers do not offer comparable levels of care. Because chemical challenges may precipitate bronchoconstriction, mental confusion, severe headaches, depression, and other disabling symptoms, these patients should not be tested in an exposure chamber on an outpatient basis.
Conventional exposure chambers do not reduce background chemical exposures for extended periods (up to several weeks) so the effects of a particular challenge in a patient can be assessed accurately. This is the central limitation of exposure chambers and the reason they should not be used to rule in or rule out chemical sensitivity. If subjects are not kept in a clean environment for several days before and during challenges, false positive responses may occur because of interfering exposures and false negative responses may occur because of masking. In contrast to an exposure chamber, an EMU would minimize interfering exposures before and during challenges, thus maximizing the reliability and reproducibility of test responses.
Availability of an EMU would allow physicians to refer a wide variety of cases in which environmental sensitivities were suspected to the unit for definitive evaluation. There physicians could observe first-hand whether a patient's symptoms improved after several days on a special diet in a clean environment. If improvement occurred, single chemicals at concentrations encountered in normal daily living as well as single foods could be reintroduced one at a time while the effects of each introduction were observed. Thus, the EMU would be a tool to determine in the most direct and definitive manner possible whether chemical sensitivities exist. Studying patients with complicated conditions like chronic fatigue syndrome or Gulf War syndrome in a conventional exposure chamber would not provide the same information, since chambers allow only short-term residence, do not control the entire range of background contaminants, and provide inadequate separation from background exposures prior to challenges.
An analogy may help illustrate the importance of controlling exposures for extended periods before challenge. If one wished to determine whether a coffee drinker's headaches were due to caffeine, it would not be adequate simply to give the person a cup of coffee and ask him how he felt. It is obvious that the individual would have to stop using caffeine for a period before a meaningful test of caffeine sensitivity could be performed. In this instance, a false negative challenge likely would be the result of failure to avoid coffee before challenge. Similarly, placing a putatively sensitive person in a conventional exposure chamber and exposing him to a low concentration of a chemical might not produce any noticeable effect. On the other hand, if this same person remained in a clean environment such as an EMU for a few days before being tested and his condition improved, one could then perform meaningful challenges.
Placing patients in an EMU would simultaneously control all three components of masking: stopping all exposures several days before challenge testing and spacing test exposures 4 to 7 days apart would preclude acclimatization or habituation; eliminating background chemical noise and allowing the effects of each challenge to subside before introducing the next one would control apposition; and excluding drugs, alcohol, nicotine, and caffeine and spacing introduction of individual foods 4 to 7 days apart would interrupt any addiction. Individual sensitivity could then be evaluated in the EMU following the postulates in Figure 7 for etiological verification.
For research purposes, challenges must be performed in a double-blind, placebo-controlled manner. Patients with chronic fatigue syndrome, migraine headaches, seizures, depression, asthma, or unexplained illnesses such as Persian Gulf illness could also be tested for sensitivities in an EMU using these postulates. Thus, the EMU could be used to determine whether particular patients with these diagnoses had a masked form of this illness.
What evidence is there that unmasking patients in an EMU and conducting challenges within a 4- to 7-day window of time is either useful or necessary? Thousands of credible patients and dozens of physicians have attempted this approach. They report that patients' symptoms resolve within a few days after they enter such a facility and that robust symptoms occur when challenges are conducted after several days of avoidance. Other evidence corroborates these observations: Withdrawal symptoms of several days' to a week's duration are known to occur in some persons following cessation of exposure to nitroglycerine (dynamite workers' headaches) (27), caffeine (18,28), nicotine, and alcohol. Note that these substances are chemically unrelated. In individuals chronically exposed to xylene (29) or ozone (30), reexposure after several days' avoidance results in robust symptoms. Foods may require one to several days to navigate the digestive tract before they are eliminated. Taken together, these observations suggest that individuals with sensitivities to multiple incitants might experience effects that linger as long as several days following initial avoidance. Thus, it may be argued that patients should be removed from their entire background of food and chemical exposures for 4 to 7 days before challenges, as Randolph first proposed (14,17).
While it is conceivable that synergistic or additive chemical combinations may be necessary to reproduce certain symptoms, this is a limitation of any form of challenge testing. Wherever possible within the bounds of safety and feasibility, chemical combinations believed to precipitate the most robust and measurable responses should be explored. However, 40 years of clinical observations, although anecdotal, suggest that single test substances may suffice for most sensitive subjects. Confirmation or refutation of these claims seems a logical first step that should precede testing of complex mixtures. Finally, because isolating patients in a hospital environment like the EMU may have unanticipated psychological consequences, early studies in this area should examine the responses of control subjects in the same environment.
Good pathological and physiological theories provide "a unified, clear, and entirely intelligible meaning for a whole series of anatomical and clinical facts, and for the relevant experiences and discoveries of reliable observers..." (31). Theories and experiments that overlook salient observations or do not control experimental conditions adequately may lead to erroneous conclusions. During the late 19th century, researchers collected sputum from patients with tuberculosis but were unsuccessful in culturing any organism. Some concluded that tuberculosis was not an infectious disease. These early investigators did not know that the tuberculin bacillus was fastidious and would grow out only after many weeks on a specialized culture medium. Correspondingly, scientists' abilities to observe and understand chemical sensitivity may depend on optimizing experimental conditions, that is, appropriate timing of challenges and use of an EMU for unmasking patients. To date, studies in this area have failed to unmask patients before challenge. When false positive and false negative responses occurred, investigators concluded that chemical sensitivity was psychogenic in origin (32,33).
In summary, features of TILT overlap those of allergy, addiction, and classical toxicity, yet TILT may be distinct from each of these. TILT appears to involve a two-step process (resembling allergic sensitization) in which persons lose specific tolerance (resembling addiction) for a wide range of common substances following a chemical exposure event (resembling toxicity). Just as the germ theory describes a class of diseases sharing the general mechanism of infection, the TILT theory of disease posits a class of chemically induced disorders characterized by loss of tolerance to chemicals, foods, drugs, and food and drug combinations. In the same way that fever is a symptom commonly associated with infectious diseases, chemical sensitivity may be a symptom associated with the TILT family of diseases. Although clinical case definitions have been developed that describe particular infectious diseases, no clinical case definition can be applied to the entire class of infectious diseases. The same may be true for TILT disorders. The fact that this phenomenon does not fit already accepted mechanisms for disease is often offered as evidence that the condition does not exist. However, the same criticism would have applied to the germ and immune theories of disease when they first were proposed. What is plausible depends on the biological knowledge of the time (34).
Looking to the future, carefully conducted epidemiological studies and animal models likely will play important roles in characterizing the initiation stage of TILT during which tolerance is lost. In the meantime, rigorous testing of the second stage of TILT, that is, the triggering of symptoms by tiny doses of chemicals, foods, drugs, caffeine, or alcohol, is needed if progress in this area is to occur. Adopting a set of relevant testable hypotheses for etiological verification will ensure the credibility of those endeavors.

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25. Warner M. Hunting the yellow fever germ: the principle and practice of etiological proof in late nineteenth-century America. Bull Hist Med 59:361382 (1985).
26. Miller CS. White paper: Chemical sensitivity: history and phenomenology. Toxicol Ind Health 10(4/5):253276 (1994).
27. Daum S. Nitroglycerin and alkyl nitrates. In: Environmental and Occupational Medicine (Rom W, ed). Boston:Little Brown and Co, 1992;10131019.
28. Griffiths RR, Woodson PP. Caffeine physical dependence: a review of human and laboratory animal studies. Psychopharmacology 94:437451 (1988).
29. Riihimaki V, Savolainen K. Human exposure to m-xylene. Kinetics and acute effects on the central nervous system. Ann Occup Hygiene 23:411432 (1980).
30. Hackney JD, Linn WS, Mohler JG, Pedersen EE, Breisacher P, Russo A. Experimental studies on human health effects of air pollutants. Arch Environ Health 30:379384 (1975).
31. Carter KC. Ignaz Semmelweiss, Carl Mayrhofer, and the rise of the germ theory. Med Hist 29:3353 (1985).
32. Leznoff A. Multiple chemical sensitivity: myth or reality? Prac Allergy Immunol 8(2):4852 (1993).
33. Staudenmayer H, Selner JC, Buhr MP. Double-blind provocation chamber challenges in 20 patients presenting with "multiple chemical sensitivity." Reg Toxicol Pharmacol 18:4453 (1993).
34. Hill AB. The environment and disease: association or causation? Proc Royal Soc Med 58:295300 (1965).
[Table of Contents]
Last Update: March 20, 1997 Search text: chemical sensitivity

Re: Dear Jonnell - testimonial in reply

Posted by JN on March 15, 1999 at 22:59:08:

In Reply to: Just a personal response to Mike posted by Johnelle on March 15, 1999 at 22:19:56:

I would like to briefly comment on your remark.
I admire Dr. Stoll for sharing with others this BB.
In no way I am trying to question at any time any diagnosis, methods, opinions, or suggestions.
I had evident severe case of MCS, FM, CFIDS.
What ever it is, whatever causes, any treatment, or diet which may healp shall be followed.
In case like this we need to do all we can do.
My injury cost me already over $ 750,000. I work with several doctors.
I have no doubt that ther is many different responses ny many different individuals.
The most important is that based on my symptoms, I want to underline my symptoms I arrived to some discoveries. Further
I went through serious research of scientific research done on thise subject. I found in my case confirmation of scientific research which were publish in US medical publications.
Some were vigoriously fought by the netwark of quacks hired by insurance companies deliberatelly confront such research as not scientific.
The ammount of research is tremendous.
The worst that some are deliberatelly ignored by such organizations as AMA, or ADA.
I arrived to conclussion that there is connection between the GUT, diet and health. There is no doubt about parasites and pathogens in the gut which not only may cause LGS, but also produce potent toxins.
For people with such severe health problems everything counts, and everything shall be done to improve.
I found also that there is relation between the flora in the gut and mercury, what was always denied.
Your experience is invaluable, and such needs to be always considered.
I will never discount your experience, and by the way I am following it to. I want to get better, and with all the nonsence which I have heard from alleged professional experts for hire, in my case I learned more.
I am also using skilled relaxation, and what relaxes me the most is to share my findings with others who may use it, should such need arrised. I became very active as the result of deliberate denial by AMA, and all nonsense which they promote.
I found tremendous benefit from this board, and I am using it personally.
I also found research which are not available to general public, and even medical doctors.
I wan t to share with others, as my contribution to society my findings, which may help others to consider and furter research the case.

I was very badly burned by SSA, while judge ruled against me. I won the appeal. My condition is very serious, but also to all of you I want to report that I reached through diet medical stabilization, and my condition substantially improved.
I am very technical, there are some issues which I do not understand, but what I have learned was sufficient to first get better, and second to fight my occupational injury.
I refered several people to this board, who are having now claims against US and CAN governments and their claims are being reviewed. Every won case in court counts, and will help others.

I found the case in New Hampshire (Kehole v. Lockheed corp) etc.
I am sharing with other what may be usefull.
My condition was critical.
I hope all of you can use parts of the informatioons, if I am to opinionated or to aggressive, I may only appologise to all of you.
What I have found the medicine has not yet confirmed.
I believe beyond doubt that Parkinson's is caused by neurotoxicity of dental mercury, only time is needed it will be proven.
Use all informations I am sharing with you, and do what you consider is right for you!
Believe me that i suffered occupational injury, and what was done to me is criminal, I am fighting and I will win.


Mike and JN

Posted by
Dawn G. on March 16, 1999 at 13:16:59:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

It is a good thing to learn about MCS and how one gets it, but... If you've got it now (as I do), you need to learn what to DO about it. Dr. Stoll has the best method to teach you to DO this. If you want more info on healing MCS specifically, Dr. Sherry Rogers books are excellent. I would recommend Tired or Toxic first.

Re: CFS, MCS, LGS, & SR. WOW !

Posted by Walt Stoll on March 16, 1999 at 13:48:15:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

Hi, MIke.

Please share with us what you are "getting" from reading "MAH, MAS". This book was written about you.

Glad to hear that you are doing the SR. What expereinces are you having with that?


Re: CFS, MCS, LGS, & SR. need more info?-

Posted by J on March 16, 1999 at 19:10:13:

In Reply to: CFS, MCS, LGS, & SR. WOW ! posted by Mike W on March 15, 1999 at 12:24:40:

Nowhere to Hide
It has been 11 years since the release of methyl isocyanate in Bhopal, India caused about 2,000 deaths and greatly heightened public awareness of the potential dangers of chemical accidents worldwide. In the aftermath of Bhopal, a variety of steps were taken in the United States to minimize the possibility that such a disastrous event would occur here, including national and local legislation and voluntary action by industrial groups.
In August of this year, the National Environmental Law Center and the U.S. Public Interest Research Group published a report, Nowhere to Hide, suggesting that we have not done enough. The authors of the report conclude that "at least one out of every six Americans lives within a vulnerable zone--the area in which there could be serious injury or death in the event of a chemical accident."
As a result of these dangers, the authors recommend that companies should be required to prepare a technology options analysis of alternatives that would eliminate or substantially reduce accident hazards, that the Chemical Safety and Hazard Investigation Board, mandated by the 1990 Clean Air Act Amendments to investigate major accidents and make recommendations for improving safety, be promptly reinstated, and that industry and government agencies should prepare and publicly communicate their worst-case accident estimates.
The authors emphasize that the report is only a screening tool for comparing disaster potential in different zip codes around the United States. The comparison is based on a calculation of the maximum vulnerable radius around each facility containing chemicals, assuming failure of all safety and mitigation systems, and total release of facility chemicals classified as Extremely Hazardous Substances by the EPA under the Emergency Planning and Community Right to Know Act of 1986. These areas are then summed for all facilities and chemicals in each zip code, and the sum is used as the measure of disaster potential for that zip code. Using this method, a zip code in Louisiana (70734), where a number of companies including BASF Corporation and Borden Chemicals and Plastics are located, ranked highest in danger potential.
Research on such methods that are used to determine population exposures from pollution sources indicates that study results can vary greatly depending on the selection of the geographical unit (e.g., zip code, county), the assumptions used in applying indirect measures of exposure (e.g., quantity released, number of simultaneous releases, and the effectiveness of barriers in mitigating releases), and other factors.
Industry and government scientists who have examined the report question whether the worst-case scenario used in the report is appropriate. They suggest that other assumptions would provide a more realistic worst-case scenario and also lead to more credible comparisons among facilities and locations.
The Chemical Manufacturers Association stated that the report "ignores the extensive risk management planning done by communities, state, and federal governments and companies in the past five years." The statement continues, the "CMA is committed to working with the public on accident prevention programs." The statement goes on to say that "the National Safety Council ranks chemical manufacturing as one of the country's safest industries."
Craig Matthiessen, of the U.S. EPA Chemical Emergency Preparedness and Prevention Office, responds that while more is being done to prevent chemical accidents than the report indicates, additional efforts are needed. These efforts, he says, should recognize that no one approach is best for all situations and that risk communication and management should focus on the things that are most likely to go wrong and how to deal with them.
One of the report's authors, Hillel Gray of the National Environmental Law Institute, said that Nowhere to Hide focuses attention on a significant problem and is the first attempt to assess the extent of the problem by evaluating relative disaster potential nationwide. He also suggests that if industry would provide more public information, the accuracy of the hazards could be better assessed and prevention of hazards from chemical accidents could be enhanced.
The authors of Nowhere to Hide consider the report a first step in analyzing the relative hazards of chemical accidents across the United States, although it does not provide quantitative estimates of individual risks. The report calls for greater sharing of information among government, industry, and the public so that a more accurate evaluation of hazards to individuals and prevention actions can be achieved, especially at the local level.
New Clinic for Chemically Related Illnesses
The Center of Excellence for Chemically Related Illness opened last August at Harborview Medical Center in Seattle, thanks to a cooperative effort between the University of Washington's Occupational and Environmental Medicine Clinic and the state's Department of Labor and Industries and Department of Health. Perhaps the first of its kind in the country, the center represents the culmination of state legislation passed in 1994 and places under one roof research efforts, educational programs, and clinical care for people exposed to chemicals.
Through a competitive process, the two state departments awarded the contract to open the center to Harborview and designated it as a center of excellence--in part because the center already operates the well-respected Occupational and Environmental Medicine Clinic. "A center of excellence is a place where a patient can go to get comprehensive treatment," says Lindsay Shuster, medical program specialist with the Department of Labor and Industries. "It's a place where patients and physicians can go early in the game. You're not sending people all over the country." According to Shuster, Harborview is ideal for such a clinic. Not only does it operate in an academic setting, it is staffed by a group of medical professionals whose combined expertise spans a spectrum of disciplines--from medical toxicology to occupational, environmental, and emergency medicine--necessary to evaluate, treat, and research chemical illnesses. However, one medical professional oversees each patient's treatment, following the case from beginning to end. In addition to standard clinic facilities, the center also has an exposure chamber for evaluating controlled exposures to known concentrations of chemicals.
Two satellite clinics, one in Spokane and one in Toppenish, will bring the center's expertise and assistance to central and eastern Washington as well. "What's really exciting," says Shuster, "is that people in rural settings can have access." The Toppenish satellite serves farm workers in a region where pesticides are routinely used. A mobile laboratory will travel the state, providing on-site environmental evaluations.
Though any individual can seek treatment at the center (through private insurance carriers), it primarily serves patients exposed to chemicals in the workplace and who have filed claims with the state. "Individual workers were feeling that their claims about exposure to work-related chemicals were not being handled in a uniform manner," says Jeffrey Burgess. Burgess, a physician who is board-certified in emergency medicine and medical toxicology, is director of the center and of the university's Occupational and Environmental Medicine program. From 1994 to mid-1995, the state processed about 3,600 claims for illnesses related to chemical exposure.
According to Burgess, a number of occupations, including manufacturing jobs that use solvents and corrosives, can expose workers to harmful levels of chemicals. "We'll be collecting data to allow us to understand better the situation in which chemical exposures occur," he says. These data provide information about a number of parameters, including demographic characteristics, pre- and post-exposure health assessments, the source and extent of exposure, and the diagnosis for chemical illness.
In addition to managing individual cases, Burgess and his colleagues will be closely watching the status of chemical exposures in general. "We'll be looking at a critical mass of patients," he says. Within a year, he hopes, the staff will be well on its way to developing diagnostic tests for evaluating specific chemical illnesses. Though many of the center's patients suffer from easily defined ailments such as occupational asthma, peripheral neuropathy, and dermatitis, some suffer from a less specific amalgam of symptoms, often classified as multiple chemical sensitivity.
Besides fulfilling clinical and research goals, the center will likely have a far-reaching impact on public policy in the state, Burgess says. Burgess and Shuster point out that the center's practical influence already extends beyond medicine by recommending protective equipment and work-site modifications to prevent returning workers from becoming ill again.
Battling EMF Reports
The debate on the health effects of electromagnetic fields (EMFs) rages as contradictory reports call for different standards. A draft report of the National Council on Radiation Protection and Measurements (NCRP) calls for exposure limits to minimize potential health hazards associated with EMFs, but it's unclear whether the prematurely publicized recommendation will survive peer review. Meanwhile, on October 9 in Sweden, government researchers offered a somewhat different assessment of the EMF problem, saying health risks don't warrant exposure limits.
According to the unofficial NCRP report, new day-care centers, schools, playgrounds, houses, and other structures should not be built in areas where ambient or "background" EMFs exceed the two-milligauss (mG) level. Furthermore, the report says, ambient EMFs near existing structures should be reduced to the 2-mG level, or at least "as low as reasonably achievable" (ALARA), within the next 10 years.
"Though not unanimous, the predominant view of the committee is to recommend the ALARA approach," the draft report states, adding that research findings "are sufficiently consistent . . . to suggest plausible connections between [extremely low-frequency] EMF exposures and disruption of normal biological processes, in ways meriting detailed examination of potential implications in human health."
NCRP President Charles B. Meinhold is urging policy makers to disregard the draft EMF report, which was leaked to the news media before clearing peer review. Chartered by Congress in 1964, the private, nonprofit group convenes committees of volunteer scientists to review existing literature and advise government agencies on various radiation issues, explains James Spahn, a senior staff scientist at the NCRP. Like all NCRP documents, the EMF report will be subjected to an extensive peer-review process, Spahn adds.
While NCRP officials are scrambling to downplay the leaked report, it's being praised by the U.S. EPA, which provided $235,000 worth of funding for the study. "This is the first comprehensive review of the world's literature on extremely low-frequency EMFs," claims EPA Project Officer Joe Elder.
But Elder can't predict whether the report will influence U.S. policy because the EPA is no longer primarily responsible for EMF research. In October 1992, Congress shifted EMF research to the U.S. Department of Energy and the NIEHS, by establishing the Electric and Magnetic Fields Research and Public Information Dissemination (EMF RAPID) Program. Dan VanderMeer, NIEHS director of program planning and evaluation and manager of the EMF RAPID Program, says the NCRP draft report won't grab his attention unless peer reviewers give it the green light. "We're not going to do anything until we have a final document," he says. "The NIEHS official position is that there are inadequate data to make any recommendations about EMF exposure levels."
W. Ross Adey, chair of the 11-member NCRP committee, declines to say much about the draft report, although excerpts appeared in the July/August 1995 issue of Microwave News. "The report speaks for itself," says Adey, a neurologist and chief of research at the Pettis Memorial Veterans Affairs Medical Center in Loma Linda, California.
In a 1993 interview with EHP, however, Adey said EMFs have clearly been shown to alter basic cellular activities. For example, he said, EMFs can disrupt the function of calcium ions, which carry signals to the interior of cells, where growth and metabolism are controlled. Also, EMFs may interfere with communication or "whispering" between cells, he said. Biological studies, Adey said, suggest that EMFs may co-promote tumor growth by working in tandem with chemical pollutants.
The draft NCRP report says numerous epidemiological studies in the United States and Europe "indicate a positive association between childhood cancers and exposure to magnetic fields" stronger than about 2 mG. Strong EMFs have also been statistically linked to increased rates of adult leukemia and brain cancer among workers in certain industries, the report says. Though biological studies have not yet revealed an "unequivocal link" between EMFs and cancer, the committee says, animal and tissue models "are consistent with an initiation-promotion (epigenetic) model of tumor formation." In light of such findings, the committee concludes, EMF exposure should be drastically reduced.
Achieving a 2-mG goal could prove extremely challenging, however, since household appliances generate much stronger fields, at least on a periodic basis. An electric shaver, for example, may produce up to 600 mG of electromagnetic energy, according to public information prepared by the NIEHS. People living within 50 feet of a 115-kilovolt electrical transmission line might be subjected to a 6.5-mG field on a continuous basis, the NIEHS says, and a 500-kilovolt line could pump out 29.4 mG at the same distance.
Thomas S. Tenforde, a vice president for the NCRP and chief scientist in the health division of Battelle Pacific Northwest Laboratory, says a 2-mG ambient exposure limit "would really shut down some technologies," such as electric trains. "There are limits to what one can consider for the sake of safety without going back to the Dark Ages," adds Tenforde, who will help review the draft report on EMFs.
Nevertheless, Constantine J. Maletskos, an NCRP consultant and executive secretary for the report, believes the EMF report will ultimately be approved--perhaps within the first half of 1996. Because NCRP reports are scrutinized by 75 council members and other experts, however, the review process can result in "vast changes," the NCRP's Spahn cautions.
Whether or not the 2-mG recommendation makes it through review, the EMF debate is destined to continue as additional reports are made public. For instance, researchers at the National Institute for Working Life (NIWL) in Stockholm say studies reveal a "credible but weak" association between certain cancers and EMF exposure, reports Kjell Hansson Mild, an associate professor for NIWL in Ume. Based on a 1995 literature review published in the European Journal of Cancer Prevention, Mild says, the advisory group endorses "prudent avoidance" of excessive EMFs, but steers clear of recommending exposure limits.
The National Research Council expects to release a status report on the EMF RAPID initiative within the next few weeks, reports John Zimbrick, director of the NRC's Board on Radiation Effects. Another NRC report on potential EMF health effects should be distributed by January or February 1996, Zimbrick says.
Also in January, the EPA hopes to release an EMF report focusing on cancer risks. Robert McGaughy, a staff member at the EPA's National Center for Environmental Assessment, says the report contains no recommendations, but conclusions about cancer risks are "similar" to the NCRP report.
Robert L. Park, a physicist and spokesperson for the American Physical Society (APS), is harshly critical of Adey and the draft NCRP report. Park, who dismissed EMF safety fears in an April 1995 statement prepared on behalf of the 45,000-member APS, lambasted the NCRP draft in a September 29 letter to the editors of Science. The NCRP document "was leaked by its authors," Park charged, "precisely because they knew its prospects for adoption by [the NCRP] lie somewhere between slim and zero."
Adey is angered by Park's allegations, and he hotly denies any involvement in the news leak. Louis Slesin, editor and publisher of Microwave News, confirms that "Adey did not leak the report, nor did any member of the committee." Described by VanderMeer as "highly respected" in his field, Adey insists that the biological evidence of EMF health effects can no longer be ignored by U.S. policy makers. Another NCRP committee member, David O. Carpenter, dean of the School of Public Health at the University of Albany, agrees, saying "the evidence is sufficiently strong" to warrant regulatory action.
New legislation to limit EMF exposure seems unlikely, however. Congressman George Miller (D-California) had proposed legislation several years ago to ban new schools and day-care centers in areas where EMFs exceed 2 mG. But that proposal was abandoned, according to Daniel Weiss, a spokesperson for Miller. "We gave up on that issue," Weiss says, citing "the inconclusiveness of the evidence."
Nor does it seem likely that the EMF issue will be resolved in the courts. In California, Marie Covalt of Orange County is suing the San Diego Gas & Electric Company, charging that high EMF levels have made her home uninhabitable. Fifteen leading scientists, including at least nine physicists and six Nobel laureates, filed an opinion on behalf of the power company, arguing that "no serious danger to health due to exposure to normal intensities of low frequency electromagnetic fields has been established." Epidemiological surveys have failed to rule out all potential risk factors, the scientists say, and biological effects aren't consistently repeatable.
Getting the Lead Out
For law enforcement officers, fear of "taking some lead" may now extend beyond their aversion to being shot in the line of duty. Officers and sportsmen alike have become increasingly concerned about the safety of outdoor firing ranges where small lead particles from the fragmentation of bullets can contaminate nearby air, soil, and water. One recent effort, however, may have produced the nation's first self-cleaning firing range.
In recent years, a number of firing ranges across the country have been closed, largely due to military cutbacks. According to Jerold Johnson, a U.S. Bureau of Mines (USBM) engineer, the military is concerned about lead from the closed ranges entering the surrounding environment. The majority of lead at these ranges comes from lead bullets fired during practice sessions: lead particles--and particles of other less toxic heavy metals such as copper and zinc--are created as the bullets strike other spent bullets lodged within a berm (the area behind the targets where the bullets land). "The main problem is not breathing the dust outside," says Johnson. "It's the lead particles getting into the soils and water."
The ultrafine lead particles can be carried by wind and collect in nearby soil. There they can be taken up by plants. A USBM report showed levels of lead in vegetation growing in contaminated soil was 100 times that of background soil samples. Lead in soil can also have adverse health effects on wildlife in the region of the shooting range. Of most concern, however, is groundwater that becomes contaminated when rainwater percolates through the lead-laden soil.
Short-term exposure to lead, one of the most widely distributed environmental neurotoxins, can cause a series of problems in adults including eye, throat, and nose irritation; headache, fever, and chills; and muscle aches. Long-term exposures can result in loss of appetite, weight loss, vomiting, irritability, fatigue, dizziness, insomnia, and visual impairment. In children, the effects of lead exposure may have much more profound consequences including impaired neurological development.
A study conducted by the Naval Facilities Engineering Service Center that characterized military shooting ranges around the country revealed that the buildup of bullets at the target and in the berms constitutes a major source of metal (mostly lead) contamination. Long-term use (years of firing thousands of bullets) of the berms resulted in lead levels of about 1% by weight of the berm; isolated pockets often held over 30% lead by weight. This lead level, determined by the Toxicity Characteristic Leaching Procedure test, exceeds the EPA criteria of 5 parts per million (ppm). The study also reported concentrations at the berms as high as 23,000 ppm for lead, 1,620 ppm for copper, and 290 ppm for zinc (background levels at the sites were listed as 16, 30, and 90 ppm respectively).
This past October, construction of a "green" firing range, designed to be safer for humans and the environment, was completed at the Salt Lake County Sheriff's Office site. Deputy Nicholas J. Roberts spent four years researching how to contain the tiny lead particles on the range in an environmentally sound manner. Roberts consulted the local USBM agency, which had worked to clean military sites around the country.
With the USBM information, Roberts and his partner Leigh Kilpack built a catch system for the lead particles. The range's new berm consists of large cement containers filled with bags of coarse-grained sand (conventional ranges use soil). The sand keeps the bullets from fragmenting as much, so there are fewer ultrafine lead particles. The berm's special design also makes it easier to remove the sand bags so that spent bullets can be removed when the bags are full.

Building a better berm. A new firing range apparatus prevents lead from entering the environment.
Photo Credit: Nicholas Roberts

In addition, a special piping and trap system is used to capture any contaminated precipitation that flows through the berm area. As the water trickles through the berm into the groundwater, it is treated with a special ion exchange method to remove lead and other metals. In the system, potentially contaminated water travels through the berm to a pipe and into a tank filled with special pellets developed by Tom Jeffers at the USBM. These pellets are made of peat moss, which has a high attraction to lead and other metals, surrounded by a porous plastic that allows the water to come in contact with the peat moss. "The peat moss has active sites that absorb the metal," explains Johnson. "Once the peat moss pellets are saturated with the metal, we can strip away the metal with a strong acid process." The beads are then put back into the tanks, and the stripped-away metal is recycled.
The new system is being used by most of the law enforcement groups in the Salt Lake County area and many groups in other areas. The USBM and the sheriff's office are currently monitoring and performing sampling at the range to determine an appropriate schedule for cleaning the beads and berms. According to Roberts, the system, which cost only several thousand dollars and is safer than removing lead-contaminated soil, provides a good solution to a widespread problem. "It's not an elaborate, expensive system," he says. "It doesn't need any [generated] power, and everything stays there on the range. And what comes off the range is 100% clean."

The National Institute of Environmental Health Sciences is one of 17 research-based institutes within the National Institutes of Health (NIH). One fact that has often been spotlighted is the NIEHS's unique location outside of the Washington, DC, metro area (where the remaining institutes are located). The NIEHS is now spotlighting its newest location on the World Wide Web at URL: http://www.niehs.nih.gov. At this site, users may benefit from the knowledge and expertise of NIEHS scientists studying the interrelationship of environmental factors, individual variability and genetic susceptibility, and age in human health and disease.

The NIEHS site offers an extensive array of public health information, research grant information, contract activities, research databases, environmental health news, the NIEHS library, and more. From the NIEHS home page, users can access additional institute home pages through hyperlinks. The Biology Home Page hyperlink allows access to a number of laboratories and programs through the Scientific Database Server including the National Toxicology Program (NTP) database. The NTP also has its own home page where users can obtain information on receiving publications such as the Biennial Report on Carcinogens and the NTP Annual Plan. The home page of the Laboratory of Quantitative and Computational Biology provides information on topics such as risk assessment and molecular modeling.
Users interested in research opportunities with the NIEHS can access the NIEHS Contracts hyperlink, which provides an electronic bulletin board of all current research and development requests for proposals (RFPs). Users may register on-line to receive information and amendments to current and future RFPs. A hyperlink to the Grants Management Branch leads users to a listing of current grants available from the NIEHS. Access to the NIEHS Superfund Basic Research and Training Program provides information on the projects, researchers, and institutions involved in this program. Training opportunities are also available through a link to the NIEHS Summers of Discovery Program.
Hyperlinks to two other sites highlight the NIEHS's commitment to providing accurate and timely environmental health information. The NIEHS EnviroHealth Clearinghouse hyperlink is now available to inform users on accessing this service. EnviroHealth provides answers to questions about current environmental health and related issues and directs users to scientists with specific expertise in different areas. The on-line version of Environmental Health Perspectives offers a sampling of research and news from the journal as well as subscription and submission information.

Re: CFS, MCS, LGS, & SR. need more info?-

Posted by
Kathy McEvoy on March 16, 1999 at 20:48:30:

In Reply to: Re: CFS, MCS, LGS, & SR. need more info?- posted by J on March 16, 1999 at 19:10:13:

Hi J,

Am thinking you must also be j and JN. I have an observation about your posts and hope you will take this in the spirit in which it is intended.

I have interest in the topics of your posts but personally find it difficult to wade through so much information. Also because of fibro fog and the fact that I do not have a technical mind, I have a hard time following all this info.

Is there any possibility that you could put some of these ideas in your own words and then possibly put a reference for the source? I do not mean any disrespect and commend you for all the hard work you must put into this bb. Only trying to make it more user friendly.


Re: CFS, MCS, LGS, & SR. need more info?-

Posted by j on March 17, 1999 at 04:12:31:

In Reply to: Re: CFS, MCS, LGS, & SR. need more info?- posted by Kathy McEvoy on March 16, 1999 at 20:48:30:

First answer Yes j=JN

The informations are from medical journals. One need to read them very slowly and several time. The "translation" could be made only by a doctor. There are some issues which I do not always yet understand myself , but I am comming very close, by reading all articles.
For the layman important is to recognise the association of the signs with causes. For the doctors it is important to recognize that such are a very serious research, and the medical science is not performed in the octors office.
I was apraised by my personal physician , who found that while he was able to provide correct diagnosis he could not fully understand some associations. For him the association of signs and symptoms with mercury poisoning was a schock, even one of his patient was found to have very heavy doses of mercury in hair smples, and urine, and now is "chelating" after removal of mercury fillings.
Consider that it is damage to central nervous system, which result in chain reaction, a chaos as result of altered functions of brain which can provide acurate control of enzymes dosage. Such consequently results in "derailing" of entire neurological and metabolic process.

Re: CFS, MCS, LGS, & SR. need more info?- (amen)

Posted by Walt Stoll on March 17, 1999 at 11:48:23:

In Reply to: Re: CFS, MCS, LGS, & SR. need more info?- posted by Kathy McEvoy on March 16, 1999 at 20:48:30:

Thanks, Kathy!

My thoughts exactly. This is all great information but we cannot even afford to archive all of it.

I hope J will keep helping but I am sure that many have the same problems we both are having with overload.


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