- Email: [email protected]
A critical analysis of multiple chemical sensitivities
Medical Hypotheses (1998) 50, 303-311 © Harcourt Brace & Co. Ltd 1998
A critical analysis of multiple chemical sensitivities JEFFREY G. THOMAS ESQ PO Box 24539, Los Angeles, CA 90024-0539, USA
Abstract - - Multiple chemical sensitivities (MCS) is a chronic condition of irritation and inflammation of sensory organs, gastrointestinal distress, fatigue, and compromised neurological function, including learning and memory deficits, unpleasant smells, tingling of nerves, and sensory discomfort. Victims report these symptoms after exposure to unfamiliar chemicals. Some studies have linked MCS to immune system dysregulation. MCS is believed to be a disease that spreads between various target organs, and is caused by sensitization to chemicals with very different structures. MCS is often attributed to free radical production and stress, which indirectly cause spreading because of damage to the immune system.
Symptoms of multiple chemical sensitivities Multiple chemical sensitivities (MCS) involves systemic discomfort, irritation and inflammation of sensory organs, flu-like respiratory symptoms, hypersensitivity of skin and epithelial lining of the gut, throat and lungs, agitation, and learning and memory loss (1). Specifically, victims report fatigue, fevers, respiratory impairment and discomfort, food allergies, gastrointestinal distress, skin irritation, dry throat, cough, eye irritation, nasal burning, acutely unpleasant smells, rash, nervousness, and loss of memory and learning deficit (2,3). Victims may experience panic, anxiety and transformation of personality (4). MCS affects people from every walk of life and every occupation: lawyers, doctors, academic pharmacologists, stockbrokers, day laborers, and secretaries (4,5). In the case of the former investment banker who made a statement to the Proceedings of the Conference on Low-level Exposure to Chemicals and Neurobiologic Sensitivity which was held in 1994
in Baltimore (6), physical and psychological deterioration caused the loss of her job and forced a move to Wyoming from New York. While in New York, she developed learning and memory deficits, and her IQ decreased. She became disabled and was unable to work at any job. She reported irritation and inflammation from handling newsprint, throat irritation and lung impairment because of smoke from wood furnaces, eye irritation, and other symptoms. MCS is linked with reports of acute sense of unpleasant smells, called cacosmia, loss of sense of smell, or anosmia, acute discomfort and irritation, and depression (1,2,7,8). The victim usually attributes the symptoms to an encounter with an unfamiliar smell or irritation, which the victim associates with exposure to a chemical ingredient in a household or office product (1,5). Because the quantities of chemicals are small, toxicologists cannot calculate dose-response relationships (9,10). Controlled studies are nearly impossible to design and conduct. The offensive chemicals include solvents such as
Received 27 July 1995 Accepted 10 April 1996
303
304 benzene, toluene and hexane, alcohols, aldehydes and ketones, which are 'inert' components of office, household products, and pesticides. The offensive chemicals are ingredients in cleaning products, new clothing, new carpets, vehicle exhaust, cosmetics, laser printers, moth balls, pesticides, paper, paints, perfume, gas stove emissions, and new particle board and plywood, among others (1,5,11,12). They may be found in mixtures with other inert ingredients, heavy metals from dyes or pesticides, and carbon monoxide or oxides of nitrogen in air pollution (1,9,10). The composition of these mixtures cannot be detected by analytical or sensory means (1). These offensive substances are individually and collectively referred to as 'multiple chemical sensitivity inducing agents,' or MCSIAs, in the context of this paper. As it is currently defined, MCS is unlike any other disease or syndrome in that the symptoms 'spread' to other MCSIAs and organs in addition to the MCSIAs that initially sensitize, and the organs that are initially sensitized. The scientific theories discussed here are neurological, physiological, and immunological in nature.
Criteria of multiple chemical sensitivities Ashford and Miller (1) have defined the elements of chemical sensitivity as follows: 1. symptoms involving many systems or every system simultaneously, and always involving central nervous system (CNS) symptoms such as fatigue, mood changes, memory and concentration difficulties; 2. different symptoms and severity in different individuals, even among those experiencing the same exposure; 3. induction or sensitization in an initial phase, involving pesticides, solvents and combustion products primarily; 4. triggering of the damage caused by sensitization, by lower levels of exposure than the initial exposures; 5. spreading of sensitivity to other chemical substances, which may or may not be similar; 6. food, alcohol, and medication intolerance in many patients. The Cullen case definition focuses on symptoms (9,10). This definition recites the multisystem effect, spreading between chemicals and systems, applicability of many diagnostic tests, acquisition from environmental sources, low triggering doses of MCSIAs and the failure of any one test to explain the result. The Cullen case definition is more appropriate to scientific research than the clinical setting (9,10).
MEDICAL HYPOTHESES
Staudenmayer (13) and Simon (14) concluded that MCS is psychological in origin. There is an overlap of more than fifty percent of MCS patients with patients who have been clinically diagnosed with anxiety, depression, or psychosomatic disorder (3). Clinical ecologists and specialists in environmental medicine recognize that immunological, neurological, and physiological symptoms of MCS have psychological components (2,4,15). But behavioral treatment of MCS is exhausting for victims, and may cause iatrogenic illness. Sensitization to MCSIAs may be genetic, infectious, or neurological (4,12). The trigger may be a neurological reflex mechanism, a stimulus to emotional memory, or a conditioned response to olfactory stimuli.
Immunological theories There is no agreement on mechanisms of immune system effect in MCS patients (1,5,9). Some studies report a general immune suppression (1,4). Some experiments reported only suppression of B cells (1), which may result from injury to B lymphocytes or T helper cells (16). The finding of exclusive B cell suppression tends to support the viewpoint that MCS involves delayed hypersensitivity caused by activated T helper cells (1,5,17). Rea (18), Vojdani (19), and Kipen et al (68) independently measured total T and B cells, T cell ratio (CD4+/CD8+), mitogenesis, and immunoglobulins of MCS patients. Vojdani (19) and Kipen et al (68) also measured natural killer (NK) cells and NK activities. The only controls were measurements of a healthy population. The results of these studies were summarized by Ashford and Miller (1) and Meggs (17). The B cell counts in MCS patients tend to be lower than in the population controls, and the mitogenesis response is decreased (1,5,17). The T cell ratio tends to be lower than in the population. However, the decreased measurements in MCS patients are within 20% of the population measurements. Ashford and Miller (1) interpreted these results as indicators of increased cytotoxic T cell activity. Baseline measurements of immune system function were not obtained in these studies, which compared population averages to MCS patient averages (11,16, 17). B and T cell subsets were not measured. These studies were ecologic in nature. In a cross-sectional study of exposure to MCSIAs, the decreases in immune system activities of humans and animals were slight (20). It proves that the capacity of a normal individual's immune system is greater than injury done by MCSIAs (20). In some studies of human response to ozone and nitrogen dioxide, which are combustion products of
305
MULTIPLE CHEMICAL SENSITIVITIES
MCSIAs and also ambient air pollutants, the results indicated immunosuppression (21). In other studies of these pollutants, the results demonstrated nonspecific immune system activation as measured by polymorphonuclear (PMN) cells and alveolar macrophages (22,23). Nonspecific activation is caused by increased permeability of the lung epithelia to antigens, tissue damage, and attraction of immunoglobulin E (IgE) to the site, followed by degranulation of mast cells and release of histamines, or atopic susceptibility (1,22, 24). The tissue damage could be caused by reactive oxygen species (ROS) or free radicals (23,25). Tolerance causes unpredictable changes in immune system markers. Naive T cells are rendered tolerant by B cells presenting antigen, but memory T cells are activated by the same B cells (26). Fuchs and Matzinger (26) tested this hypothesis in C57BL/10 mice and proved that naive T cells are rendered tolerant to spleen cells from the male mouse because the B cell cannot provide a costimulatory signal. The memory T cell does not require a costimulatory signal and is activated. Also, as hypothesized by Fuchs and Matzinger, there may be tolerance in the 'low concentration zone' where antigen is presented only by B cells, activation in the moderate zone where antigen is presented by B cells and professional antigenpresenting cells, and tolerance in the high concentration zone where excess antigen is presented by B cells. If the Fuchs and Matzinger hypothesis of tolerance is true, it may explain why some MCS patients have low B cell counts and experience delayed hypersensitivity at the same time. A molecular experiment might test the theory of induced tolerance of naive T cells in MCS patients (26). Such a study should examine the behavior of T cell subsets of delayed hypersensitivity cells (Tdth), suppressor inducer cells (CD4+), subsets of T memory (CD45 +) and B memory cells, and mitogenesis (27-29). The investigator may identify the chemicals to which MCS study patients are exposed, in order to validate controls. Based on prior experiments with exposure to MCSIAs in cell cultures, laboratory animals, and people, there are many alternative explanations of immune response in MCS. For example, in animals exposure to dimethylbenzanthracene (DMBA) suppressed antibody (Ig) production, T cell cytotoxicity, and NK cell activity (30). DMBA is a polynuclear aromatic hydrocarbon (PAH). The mechanism was destruction of T helper cells, but the Tdth subset was not measured. In experiments with ozone in vitro, Becker (21) found that lymphocytes produce less Ig in response to T cell dependent mitogen, but response to the polyclonal B cell activator is the same. This experiment may prove that ozone does suppress the specific immune response, if concentrations are high
enough. Given the results of the other experiments with air pollution, it seems unlikely that ozone destroys the T helper cell or mutates its DNA. It is more likely that ozone damages the cell membrane. Diaz-Sanchez et al (31) measured responses to persons exposed to PAHs in clinically administered nasal lavages. The subjects were Los Angeles residents who are chronically exposed to PAHs in particulate smog. Saxon et al (31, and personal communication) found that IgE production was increased in subjects as compared with controls. It seems unlikely that these PAHs are any less mutagenic than DMBA. However, at the concentrations used in this study, they were not mutagenic, because Saxon measured increases in IgE mRNA. Saxon's results may be explained as an adjuvant effect (16,32), or as a tolerance mechanism (5,26,33). In normal persons, coping promotes immune response after an initial suppression caused by chemical exposure or stress (24). In a study of chronic stress in people living near the Three Mile Island nuclear power plant which was concluded six years after the radiation accident, the population had the same number of T helper cells as the comparison group, more neutrophils, and fewer B cells and T suppressor cells (11). Active coping did not occur, and the downward trend in cell proliferation reversed with time. The number of suppressor cells was less than normal. The immune response to a latent virus was normal at all times. Vojdani et al (19) reported the discovery of T cell epitopes for various chemicals such as benzene and toluene, and a slight increase in autoantibodies. Autoimmunity is a more appropriate hypothesis for MCS than the possibility of a T cell receptor for MCSIAs (16,34). Molecular mimicry in this situation would involve similarity of the amino acid sequence of a virus envelope and a career molecule for MCSIAs as haptens, and a cross-reaction between antibodies to the virus and the carrier molecule (34,35). MCS is not clinically recognized by immunologists. Jewett demonstrated that persons with food allergies cannot distinguish between a placebo and the putative allergen in double-blind provocationneutralization (36). Wolf (37) has suggested that MCS diagnosis should be confirmed with a blind provocation test of hypersensitivity.
Neurological theories
Kindling, time-dependent sensitization, and pharmacology Most biological processes cause a habituating, or tolerant, response - i.e. one that diminishes in
306 response to repeated stimuli. MCS involves a sensitization response that is enhanced by repeated exposures. MCSIAs probably breach the blood-brain barrier through the olfactory nerve, and directly cause sensitization of the CNS (1,2). The seizure-like activity which results is known as kindling. Kindling is associated with epilepsy in laboratory animals. Animal models of kindling were first developed to explain the nonhomologous process of bipolar depression in humans. MCSIAs also cause time-dependent sensitization (TDS), which is a deterioration in stability of central nervous system, endocrine, and behavioral markers without kindling (9,15,38,39). Kindling and TDS may result from a single exposure to MCSIAs (39,40). Repeated exposures to MCSIAs can cause spontaneous seizures (39,40). The kindling apparently causes deterioration of long-term potentiation, which is a mechanism of efficient learning and memory (2,15,39). Kindling may cause sensory irritation and deficits in learning and memory. Bell proved that pesticides and other MCSIAs cause kindling in laboratory animals (2,15). Other investigators have obtained similar results with pharmaceuticals and MCSIAs (38-40). The kindling occurs in the limbic structures which are sites of short-term memory and association functions, chiefly the amygdala and hippocampus. Glutamateresponsive neurons are common in the limbic system, and glutamate levels correlate with kindling (39). Many neuropeptides of hypothalamic and extrahypothalamic origin are found in the hippocampus. Kindling may explain the spreading of MCS, because kindling 'spreads' between target organs and between chemicals. MCS almost always involves variations in neuroendocrine parameters. Bell has suggested that MCS spreads between chemicals and target organs because of corticotropin releasing hormone (CRH) release from the hypothalamus during kindling (15). The pathways of CRH, and its functions in the limbic system, are very complex. Bell has postulated an interaction of excitotoxicity and CRH action, which is based on the evidence of CRH interaction with cytokines, neurotransmitters, neuropeptides, and hormones (see below). Speculation about pharmacologic models of MCS has focused on glutamate receptors in the hippocampus, kindling, and excitotoxicity. When norepinephrine is released in the central nervous system during stress and binds to hippocampal neurons, it reduces the hyperpolarization afterdischarge of potassium ion (K+) (24,41). Norepinephrine potentiates glutamate neurotransmitter activity as a result (42). When toxic chemicals are bound to the GABAa receptor, the response to glutamate is disinhibited
MEDICAL HYPOTHESES
(24,43). Glutamate causes degranulation of mast cells (24). Degranulations of mast cells, mucus producing cells, and mononuclear cells in the lungs cause delayed hypersensitivity (24). A pharmacologic model should account for the 'masking' phase of MCS, which is biphasic. The cyclodiene pesticides dieldrin and lindane, among others, bind tightly to the picrotoxin site of GABAa receptors in CFS patients (43). GABA-induced chloride influx is inhibited (43), and the victim suffers convulsions. Doses which are too low to cause convulsions are anxiogenic, which probably results from nonspecific binding to benzodiazepine receptors (44). The conclusive effect corresponds to the sensitization phase of MCS, and the anxiogenic effect corresponds to the masking phase. The blockage of benzodiazepine receptors by pharmacologic agents which do not bind tightly to the picrotoxin site of the GABAa receptor causes a potentiation of glutamate at n-methyl-d-aspartate (NMDA) receptors, which causes an increase in long-term potentiation, or excitotoxicity if glutamate concentrations are excessive (24,39,43). When benzodiazepine receptors are nonspecifically blocked by some MCSIAs, defensive behavior is precluded, and coping strategies are activated (43,45). The coping strategy may mask the sensitization and the excitotoxicity. Although cyclodiene pesticides bind to the picrotoxin site of the GABAa receptor in CFS patients, CFS patients do not manifest substantial cognitive deficits (3,43). Whether this is the result of exposure to fewer MCSIAs or the greater adaptive ability of CFS patients is unknown. The benzodiazepine receptor is not implicated in cognitive activity. In MCS patients, exposure to organophosphate pesticides damages cholinergic neurotransmitter input to the dentate gyrus of the hippocampus, where cholinergic activity is modulated by GABA (32). The damage to cholinergic input affects adrenergic neurotransmitter input to the dentate gyrus, and learning and memory deficits may result (46). Furthermore, if dopamine receptors are stimulated, this neurotransmitter causes other behavioral symptoms of MCS such as lack of spontaneity and stereotypical behavior (40). Neuromodulation is the result of allosteric binding of neurotransmitters to receptors (41). The GABAa receptor has an allosteric steroid receptor (43). The binding of picryl chloride at the GABAa receptor alters the balance between Type 1 and Type 2 corticosteroid receptors (43). The ultimate physiological effect is unknown, but it may be important to MCS. The effect of diet cannot be neglected. Fatty acids and cholesterol in the diet are anti-inflammatory
307
MULTIPLE CHEMICAL SENSITIVITIES
because the body responds with diminished production of B 4 leukotrienes and interleukin-1 (IL-1) (42). Fatty acids and cholesterol in the diet reduce lymphocyte and neutrophil (PMN) responses as measured by mitogenesis (42). However, excitotoxicity causes degranulation of mast cells and inflammation (24). Fatty acids and cholesterol depress glucocorticoid formation, which abates the suppression of excitotoxicity (42).
factor (elF-2) (52). It is stimulated by interferon. The phosphorylated eIF-2 blocks the exchange of GDP for GTP, replication of the virus, and may suppress tumors (52,53). Concurrently, PKR phosphorylates the MAD-3 protein of the I-r~B family of inhibitors of NF-lcB (53). The phosphorylated protein disassociates from NF-~B, which enhances transcription in the cell nucleus. PKR activity may be relevant to MCS because NF-~B causes inflammation in response to ROS and free radicals (54).
Signal transduction Some mechanisms for signal transduction are relevant to MCS neurotoxicity. The first such theory is the signal transduction response to tumor necrosis factor-~ (TNF-c0, IL-1, and ultraviolet (UV) light, which are all stimulated by environmental stress (16). The protein kinase JNK is activated by phosphorylation of Thr and Tyr by a dual-specificity mitogenesis-activated protein (MAP) kinase, JKK. INK phosphorylates the transcription factor c-Jun and the protein kinase p38 (47). Activity of the Fos-Jun heterodimer is linked to long-term potentiation, and synaptic plasticity (40). Kandel has studied the mechanism of long-term potentiation in the hippocampal neuron, in response to an influx of glutamate (48). In long-term learning, postsynaptic cells are depolarized, the n-methyl-daspartate (NMDA) receptor is activated, calcium ion (Ca 2+) influx into the cell follows, adenylate cyclase and cyclic adenosine monophosphate (cAMP) are stimulated, and the catalytic subunit of protein kinase A (PKA) translocates to the nucleus. In the nucleus, PKA activates a MAP kinase and the CREB transcription factor, which enhances production of messenger ribonucleic acid (mRNA) and protein synthesis for neuron synapses. Kandel's group have confirmed the results of these cellular studies with knockout mice experiments (49). The knockout mice cannot synthesize protein for the synapses, and cannot alter their behavior in response to appropriate stimuli. For these molecular mechanisms to cause MCS, glutamate levels must first be upregulated. If there is a defect in the CRH response to stress as hypothesized for MCS patients (2), this defect could cause increased glutamate levels. Furthermore, both glucose and glutamine are energy sources for lymphocytes (42). If glutamine is diverted to synthesis of glutamate, a shortage of glutamine for lymphocyte metabolism may result. Acetate is a metabolic product of some MCSIAs (50), and a substrate for glutamate synthesis (51). Protein kinase R (PKR) is a RNA-activated kinase which inhibits protein synthesis by phosphorylating a subunit of the essential polypeptide chain initiation
Markers MCS patients often report sensations of anosmia, cacosmia and dysosmia (2,7,21). Anosmia is a loss of the sense of smell; and cacosmia is perceiving a smell as unpleasant which most people perceive as pleasant (7). Dysosmia is partial anosmia. Cacosmia is associated with memory loss, and advanced age (2,8). MCSIAs which are slightly soluble in water, i.e. organic solvents, may be concentrated in the olfactory mucus relative to ambient concentrations (7,46). MCSIAs are also metabolized to olfactory stimulants and irritants by enzymes that are abundant in olfactory epithelium, especially cytochrome P450 (46). There are millions of olfactory neurons, which are continually replaced. Allelic exclusion contributes to the genetic diversity (7,55). Exposures to some MCSIAs damage olfactory epithelia (56-58). Subsequently, function and morphology of the epithelia regenerate, but there is residual damage. Hurtt et al suggested that the residual damage could be the reason for specific anosmia in humans (58). However, Hurtt et al concluded that if olfactory tissue is only partially destroyed, neuropsychological testing is meaningless. Therefore olfactory response is not a wholly reliable marker of MCS. Brain scans have provided evidence of excitotoxicity, in abnormal single positron emission computerized tomography (SPECT) and positron emission tomography (PET) scans, and electroencephalograms (EEG) and evoked olfactory potentials (EOP) of MCS patients (9,39,59). The subjects manifested MCS symptoms and intermediate markers of excitotoxicity (59). The brain mapping techniques are the most reliable clinical markers of neurotoxicity so far. MCSIAs may stimulate the trigeminal nerve endings which are located in the olfactory passages, and cause a conditioned response in long-term memory in the hippocampus (2,15). A conditioned response which involves cytokines, interferon- a, and neurotransmitters has been studied in laboratory animals (46). The results of these studies may define markers of MCS in the future.
308 Other neurotoxicities
The bidirectional communication between lymphocytes and the hypothalamic and pituitary axis (HPA) is well established. Lymphocytes have receptors for hormones, neurotransmitters, and lymphokines which are produced by the HPA or peripheral cells (29,46,60-62). Autocrine and paracrine interactions are implicated in these receptor-mediated events. In nonstressful situations, the cortisol which is produced in the adrenal gland has negative feedback on the pituitary gland, which decreases norepinephrine production and increases corticotropin (ACTH) production (24). ACTH suppresses the immune system (28,61). Cortisol suppresses the immune system, and causes negative feedback on ACTH production in the pituitary (24,46,60-62). When there is stress, norepinephrine increases in the circulation and so does ACTH (46,60-62). Coping reinstates negative feedback (28,42,46). Corticotropin-releasing hormone (CRH) release from the hypothalamus stimulates the production of neuropeptides, chiefly substance P, which irritates the sensory organs (38). CRH release in the central nervous system is associated with norepinephrine release solely in stressful situations (42,50). CRH stimulates the release of catecholamines and opioid neuropeptides (24,42). In stressful situations, timedependent sensitization is blocked by a CRH antagonist (38). A CRH antagonist causes excitotoxic-like symptoms involving irreversible impairment of cognitive functions in laboratory animals (24). MCS and CFS patients report increased symptoms under stress (4,8,9,14). Since norepinephrine potentiates the effect of glutamate neurotransmitter in the central nervous system, this result is expected. Epinephrine stimulates the production of lactate (50); and lactate is implicated in panic syndrome. However, neither lactate, norepinephrine, nor epinephrine is validated as a marker of chronic stress. In CFS patients, reduced pituitary and adrenal feedback of cortisol to the hypothalamus cause low CRH levels and low cortisol (3). There are no published results for MCS patients, but the measured results are similar. CFS and MCS patients may both suffer from a defect in the ability of CRH to enhance negative feedback of cortisol, and the stress may become chronic in this manner. ROS and free radicals have an additive effect. Some MCSIAs cause free-radical damage in MCS patients (9,18), which may potentiate the excitotoxicity of MCSIAs (42,63,64). ROS and free radicals cause hyperreactive airways (25,63). Investigators are examining the potentiating effect of nitric oxide on glutamate toxicity (64).
MEDICAL HYPOTHESES
A mixture of toluene and benzene is immunosuppressive, but benzene causes more suppression than the mixture (33,65). The same mixture has additive effect in the CNS and causes depression (66). The opposite effects may be caused by differential effects of ROS and free radicals in the nervous and immune systems, especially with regard to interaction with excitotoxins and glucocorticoids (25,46). Excitotoxicity is linked to significant changes in neuropeptide activity including substance P (24). Substance P is stored in vesicles, which are located near or in excitatory neurons. The MCSIAs ozone and nitrogen dioxide damage the airway epithelium and expose non-adrenergic, non-cholinergic (NANC) sensory nerve endings (9,67). The nerve endings release substance P, which causes bronchoconstriction and hyperreactivity in animals and humans (9,24,67). Substance P stimulates mast cells, eosinophils and macrophages, and causes inflammation of the lung. When cholinergic and adrenergic neurotransmission pathways are blocked by pharmaceutical drugs, allergens and cigarette smoke cause pulmonary resistance (63). Both inhibitory NANC neurons and excitatory NANC neurons are found in the bronchial epithelia (56). Excitatory NANC neurons cause irritant-induced asthma and adult respiratory distress syndrome (ARDS) in research studies (56,63,67). Stimulation of excitatory NANC neurons by substance P, or malfunction of inhibitory NANC neurons by an unknown mechanism, could cause asthma and respiratory distress in MCS patients. Opioid neuropeptides such as 13-endorphin and the enkephalins counteract the effects of substance P in vitro (46). Apparently opioids act as neuromodulators, because low doses of exogenously administered opioids cause kindling-like convulsions in vivo (15). The opioid neuromodulation may explain the paradoxical effects of organic solvents. Exposure to organic solvents in the moderate range of 250-500 parts per million (p.p.m.) causes giddiness and hyperactivity, and an apparent increase in locomotor activity (65). Very-high-level exposure causes depression and narcosis, because of decreased neurotransmitter activity (65). Activated macrophages produce the inflammatory cytokine IL-1 (25,46,60,61). IL-1 enhances opioid receptor binding in the brain; and the interaction with IL-1 demonstrates the neuromodulatory effect of opioids (46,61). IL-1 stimulates production of CRH in the hypothalamus. Other considerations Eosinophilia promotes formation of free radicals (42). Eosinophils damage epithelia, and are recruited by
309
MULTIPLE CHEMICAL SENSITIVITIES
histamine mediators released by mast cells (24,42). However, eosinophils are rarely monitored in MCS patients, and when these cells are monitored there is no eosinophilia. Researchers have long speculated that the 'body burden' of stored fat containing chlorinated pesticides and solvents causes the classic symptoms of MCS, when stress mobilizes the pollutants from the stored fat and causes their release to the circulation (18). An inadequate diet and mobilization of chemicals from stored fat may explain simultaneous 'masking' and spreading of MCS symptoms and immune suppression, because supplies of zinc, iron and copper are also very important to an activated immune system (64). Inadequate diet and mobilization of fat stores do not explain simultaneous MCS symptoms and immune suppression. However, immune suppression is not confirmed as a universal symptom of MCS patients, and it is possible that the mobilization of pollutants overwhelms the metabolism. Certainly, some pollutants such as ethanol induce the cytochrome P450 system (66). Xenobiotic-induced disease states alter peripheral immune cell responses to the neurotransmitter acetylcholine (46). The 'environmental' diseases sometimes enhance cytokine production in immune cells, including IL-1 and IL-2; and upregulation of these cytokines may cause mental depression (46). It may be possible to demonstrate a conditioned response to stress in MCS patients, involving interactions of cytokines and neurotransmitters (24,42,46). In in vitro experiments, stress and exposure to toxic chemicals cause a downshift of natural killer cell activity which is associated with the passage of interferon-beta (IFN-[3) across the blood-brain barrier to the CNS (46). This is a conditioned response in some animal models.
3.
4.
5.
6.
7.
Research hypotheses The following is a list of likely research hypotheses for future experiments. These hypotheses are derived from the discussion in the paper. 1. Free-radical concentrations may be measured in epithelial ceils derived from MCS patients after exposure to MCSIA. Correlations of free-radical concentrations, glutamate levels, and neutrophil and eosinophil activities might be evaluated. Freeradical concentrations may be measured using scavenger agents. Results could be compared for CFS and MCS patients. It would be instructive to compare results for MCS and CFS patients. 2. The bidirectional communication between the immune system and nervous systems may be
8.
9.
investigated in MCS patients. Correlations of the CD4+/CD8 + cell ratio with activity of c~ and [3 adrenergic receptors and norepinephrine levels may be evaluated in vitro after exposure to MCSIA. The effect of various cytokines on the T cell ratio could be demonstrated. Markers of immune system effect can be improved with measurements of the effects of MCSIAs, including irritants and mutagens, using standard immune cell experiments. An experiment could also be performed on adrenalectomized mice to determine the immune suppression which is caused by MCSIA exposure. MCS symptoms may be correlated with routes of exposure and differential impacts on the subsets of T helper cells, including Tdtu and suppressor inducer cells, and adhesion cells. The experiment should include separate measurements of naive T cell and memory T cell activities. A variation of this experiment might involve observations under mild escapable and inescapable stress. The regulation of genes which cause inflammation, chiefly NF-k[3, may be studied in epithelial cells in vitro. Correlations of the activity of this gene with cyclic adenosine monophosphate (cAMP) and norepinephrine levels can be evaluated, using [3 receptor blockers. The impact of the tumor suppressor gene PKR may be measured in mice with a 'knocked-out' gene. The mice can be challenged with antigen in the presence of pollutants. Immune response to latent viruses, such as the herpes simplex virus used in the Three Mile Island experiment, may be measured in vitro. If there is response, it may demonstrate integration of the virus into the host genome. Molecular mimicry of viruses and the genes of target organs can be evaluated. Kindling and TDS for various pesticides and MCSIAs which have been previously analyzed in laboratory animals may be studied in the same laboratory animals to determine the effect of metabolism by cytochrome P-450 in the olfactory epithelia. The impact of health status on TDS and kindling should be measured. Brainwave activity of laboratory animals may be measured with PET and MRI scans after exposure to MCSIA. The brainwave activities may be correlated with levels of neurotransmitters in the brain. Markers which are used clinically for purposes of diagnosing other conditions, such as phenylalanine for depression, bronchoalveolar lavage for lung impairment, and other amino acids should be investigated in MCS patients for correlations with symptoms.
310
Conclusion Many interesting explanations for MCS and chemical-induced toxicity in general have been advanced. The theories of MCS as explained in this paper, are currently undergoing formulation and refinement. The author hopes that this paper may make a contribution to the understanding of MCS, and that the suggestions for future research will provide inspiration to scientists who are interested in this subject.
Acknowledgments I would like to acknowledge my faculty advisor, Dr Michael D. Collins of the UCLA School of Public Health for generous advice.
References 1. Ashford N, Miller C. Chemical Sensitivity: Low Exposures, High Stakes. Van Nostrand Reinhold, 1992. 2. Bell I. Neuropsychiatric aspects of sensitivity to low-level chemicals: a neural sensitization model. Toxicol Industr Health 1994; 10(4-5): 277-312. 3. Buchwald D, Garrity D. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med 1994; 154(18): 2049-2053. 4. Heuser G. Diagnostic Markers of Multiple Chemical Sensitivity, Addendum to Biologic Markers in Immunotoxicology 117-38. Washington, DC: National Research Council, 1992. 5. Hileman B. Multiple chemical sensitivity. Chem & Engr News 1991; 69(29): 26-42. 6. Wilson C. Chemical sensitivity - - one victim's perspective. Toxicol Industr Health 1994; 10(4-5): 319-322. 7. Dory R L. Olfaction and multiple chemical sensitivity. Toxicol Industr Health 1994; 10(4-5): 359-368. 8. Shnsterman D, Sheedy J E. Occupational and environmental disorders of the special senses. Occup Med 1992; 7(3): 515-542. 9. Sparks P J e t al. Multiple chemical sensitivity syndrome: a clinical perspective, I: case definition, theories of pathogenesis and research needs. J Occup Med 1994; 36(7): 718-730. 10. Sparks P J e t al. Multiple chemical sensitivity syndrome: a clinical perspective, II: evaluation, diagnostic testing, treatment and social considerations. J Occup Med 1994; 36(7): 731-737. 11. McKinnon W, Weisse C S, Reynolds C P, Bowles C A, Baum A. Chronic stress, leukocyte subpopulations, and humoral response to latent viruses. Health Psychol 1989; 8(4): 389-402. 12. Samet J, ed. Environment controls and lung disease, report of the ATS Workshop on Environment Controls and Lung Disease. Am Rev Respir Disease 1990; 142(4): 915-939. 13. Staudenmayer H, Selner M E, Selner J C. Adult sequelae of childhood abuse presenting as environmental illness. Ann Allergy 1993; 71(6): 538-546. 14. Simon G E, Daniell W, Stockbridge H, Claypoole K, Rosenstock L. Immunologic, psychological and neurophysiological factors in multiple chemical sensitivity. Ann Intern Med 1993; 19(2): 97-103. 15. Bell I R, Schwartz G E, Peterson J M, Amend D, Stini W A. Possible time-dependent sensitization to xenobiotics: selfreported illness from chemical odors, foods, and opiate drugs in an older adult population. Arch Env Health 1993; 48(13): 315.
MEDICAL HYPOTHESES
16. McGrath K G, Zeiss C R, Patterson R. Allergic reactions to industrial chemicals. Clin Immunol Rev 1983; 2(1): 1-58. 17. Meggs W J. Multiple chemical sensitivities and the immune system. Toxicol Industr Health 1992; 8(5): 203-214. 18. Rea W. Chemical Sensitivity, Vol. 1. Boca Raton: CRC Press, 1992. 19. Vojdani A, Ghoneum M, Brautbar N. Immune alteration associated with exposure to toxic chemicals. Toxicol Industr Health 1992; 8(5): 239-257. 20. Hong R. Effect of environmental toxins on lymphocyte function: studies in rhesus and man. Ann Allergy 1991; 66(6): 474-480. 21. Becker S. Ozone effects on human immunoglobulin production. J Toxicol Env Health 1990; 34(3): 353-366. 22. Devlin R B. Exposure of humans to ambient levels of ozone. Am J Respiratory Cell Mol Biol 1991; 4(1): 72-81. 23. Friedman M E, Madden M C, Samet J M, Koren H S. Effects of ozone exposure on lipid metabolism in human alveolar macrophages. Env Health Perspectives 1992; 97: 95-101. 24. Djuric V J, Bienenstock J. Learned sensitivity. Ann Allergy 1993; 71(1): 5-14. 25. Whitacre C M, Cathlart M K. Oxygen free radical generation and regulation of proliferative activity of human mononuclear cells responding to different mitogens. Cell Immunol 1992; 144(2): 287-295. 26. Fuchs E J, Matzinger P. B cells tuna off virgin but not memory T cells. Science 1992; 258(5085): 1156-1159. 27. Munson A E, McLay J A, Cat W. Approaches to immunotoxicology studies with emphasis on chemical-induced immunomodulation. Ann Allergy 1991; 66(6): 505-518. 28. Sheridan J F et al. Restraint stress differentially affects antiviral cellular and humoral immune responses in mice. J Neuroimmunol 1991; 31(3): 245-255. 29. Whitacre C M. Immunology: a state of the art lecture. Ann NY Acad Sci 1990; 594: 1-16. 30. Dean J H, Ward E C, Murray M H, Lauer L D, House R V. Mechanisms of dimethylbenzanthracene-induced immunotoxicity. Clin Physiol Biochem 1985; 3(2-3): 98-110. 31. Diaz-Sanchez D, Dotson A R, Takenaka H, Saxon A. Diesel exhaust particles induce local IgE production in vivo and alter the pattern of IgE messenger RNA isoforms. J Clin Invest 1994; 94(4): 1417-1425. 32. Davenas E, Beneveniste J e t al. Human basophil degranulation triggered by very dilute antiserum against IgE. Nature 1988; 333(6176): 816. 33. Hsieh G C, Sharma R P, Parker R D. Hypothaiamic-pituitaryadrenocortical axis activity and immune function after oral exposure to benzene and toluene. Immunopharmacology 1991; 21(1): 23-32. 34. Gleichmann E, Kimber I, Purchase I F. Immunotoxicology: suppressive and stimulatory effects of drugs and environmental chemicals on the immune system. Arch Toxicol 1989; 63(4): 257-273. 35. Merrill J E, Jonakait G M. Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease. FASEB J 1995; 9(8): 611-618. 36. Jewett D L et al. A double-blind study of symptom provocation to determine food sensitivity. N Engl J Med 1990; 323(7): 429-433. 37. Wolf C. Multiple chemical sensitivities - - is there a scientific basis? Int Arch Occup Env Health 1994; 66(4): 213-216. 38. Antelman S M. Time-dependent sensitization in animals: a possible model of multiple chemical sensitivity in humans. Toxicol Industr Health 1994; 10(4-5): 335-342. 39. Gilbert M E. The phenomenology of limbic kindling. Toxicol Industr Health 1994; 10(4-5): 343-358. 40. Weiss S. Caveats in the use of the kindling model of affective disorder. Toxicol Industr Health 1994; 10(4-5): 421-448.
MULTIPLE CHEMICAL SENSITIVITIES 41. Bloom F E. Neurotransmitters: past, present and future directions. FASEB J 1988; 2(1): 32-41. 42. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993; 329(17): 1246-1253. 43. Corrigan F M, MacDonald S, Brown A, Armstrong K, Armstrong E M. Neurasthenic fatigue, chemical sensitivity and GABAa receptor toxins. Meal Hypotheses 1994; 43(4): 195-200. 44. Leslie J C, Liam T, Shephard R A. Conditioned suppression and the effect of pentobarbital with picrotoxin, flumazenil and R05-3663. Psychol Rec 1995; 45(2): 299-307. 45. Kalin N H. The nenrobiology of fear. Sci Am 1993; 268(5): 94-101. 46. Fuchs B, Sanders V M. The role of brain-immune interactions in immunotoxicology. Crit Rev Toxicol 1994; 24(2): 151-176. 47. Davis R J. MAPKs: new JNK expands the group. Trends Biochem Sci 1994; 19(11): 470-473. 48. Kandei E, Abel T. Neuropeptides, adenyl cyclase, and memory storage. Science 1995; 268(5212): 825-826. 49. Grant S G N e t al. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 1992; 258(5090): 1903-1910. 50. Iatropoulos M. Endocrine considerations in toxicologic pathology. Exp Toxicol Pathol 1993-4; 45(7): 391-410. 51. Ishizaka S, Kikuchi E, Higashino T, Kinoshita K, Tjujii T. Effects of acetate on the immune system of mice. Int J Immunopharm 1990; 12(1): 135-143. 52. Wek R C. eIF-2 Kinases: regulators of general and genespecific translation initiation. Trends Biochem Sci 1994; 19(11): 491-496. 53. Clemens M. Suppression with a difference. Nature 1992; 360(6401): 210-211. 54. Xia C, Hu J, Ketterer B, Taylor J B. The organization of the human GSTP-1 gene promoter and its response to retinoic acid and cellular redox status. Biochem J 1996; 313 (Part 1): 155-161. 55. Lancet D. Exclusive receptors. Nature 1994; 372(6504): 321-322. 56. Barnes P J. Neural mechanisms in asthma. Br Med Bull 1992; 48(1): 149-168.
311 57. Cone J A e t al. Persistent respiratory health effects after a metam sodium pesticide spill. Chest 1994; 106(2): 500-508. 58. Hunt M E , Thomas D A, Working P K, Monticello T M, Morgan K T. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: pathology, cell kinetics, and olfactory function. Toxicol Appl Pharmacol 1988; 94(2): 311-328. 59. Heuser G, Mena I, Atamos F. NeuroSPECT findings in patients exposed to neurotoxic chemicals. Toxicol Industr Health t994; 10(4-5): 561-572. 60. Black P H. Psychoneuroimmnnology: brain and immunity. Sci & Med (Sci Am) 1995; 2(6): 16-25. 61. Black P H. Central nervous system-immune system interactions: psychoneuroendocrinology of stress and its immune consequences. Antimicrob Agents Chemother 1994; 38(1): 1-6. 62. Black P H. Central nervous system-immune system interactions: effect and immunomodulatory consequences of immune system mediators on the brain. Antimicrob Agents Chemother 1994; 38(1): 7-12. 63. Nishiwaka M, Ikeda H, Fukuda T, Suzuki S, Okubo T. Acute exposure to cigarette smoke induces airway hyperresponsiveness without airway inflammation in guinea pigs. Am Rev Resp Disease 1990; 142(1): 177-183. 64. Serog P. Clinical status of nutritional origin involving immune deficiency. Food Addit Contain 1990; 7(Suppl. 1): $87-$93. 65. Hsieh G C et al. Subclinical effects of groundwater contamination - - 1I: alteration of brain monoamine neurotransmitters by benzene in CD-1 mice. Arch Env Contamination Toxicol 1988; 17(6): 799-805. 66. Lang L. Strange brew: assessing risk of chemical mixtures. Env Health Perspectives 1995; 103(2): 142-145. 67. Stretton D. Nonadrenergic non-cholinergic neural control of the airways. Clin Exp Pharmacol Physiol 1991; 18(10): 675-684. 68. Kipen H e t al. Immunologic evaluation of chemically sensitive patients. Toxicol Industr Health 1992; 8(5): 125-135. 69. Holt P G e t al. Defence against allergic sensitization in the healthy lung: the role of inhalation tolerance. Clin Exp Allergy 1989; 19(3): 255-262.
A critical analysis of multiple chemical sensitivities JEFFREY G. THOMAS ESQ PO Box 24539, Los Angeles, CA 90024-0539, USA
Abstract - - Multiple chemical sensitivities (MCS) is a chronic condition of irritation and inflammation of sensory organs, gastrointestinal distress, fatigue, and compromised neurological function, including learning and memory deficits, unpleasant smells, tingling of nerves, and sensory discomfort. Victims report these symptoms after exposure to unfamiliar chemicals. Some studies have linked MCS to immune system dysregulation. MCS is believed to be a disease that spreads between various target organs, and is caused by sensitization to chemicals with very different structures. MCS is often attributed to free radical production and stress, which indirectly cause spreading because of damage to the immune system.
Symptoms of multiple chemical sensitivities Multiple chemical sensitivities (MCS) involves systemic discomfort, irritation and inflammation of sensory organs, flu-like respiratory symptoms, hypersensitivity of skin and epithelial lining of the gut, throat and lungs, agitation, and learning and memory loss (1). Specifically, victims report fatigue, fevers, respiratory impairment and discomfort, food allergies, gastrointestinal distress, skin irritation, dry throat, cough, eye irritation, nasal burning, acutely unpleasant smells, rash, nervousness, and loss of memory and learning deficit (2,3). Victims may experience panic, anxiety and transformation of personality (4). MCS affects people from every walk of life and every occupation: lawyers, doctors, academic pharmacologists, stockbrokers, day laborers, and secretaries (4,5). In the case of the former investment banker who made a statement to the Proceedings of the Conference on Low-level Exposure to Chemicals and Neurobiologic Sensitivity which was held in 1994
in Baltimore (6), physical and psychological deterioration caused the loss of her job and forced a move to Wyoming from New York. While in New York, she developed learning and memory deficits, and her IQ decreased. She became disabled and was unable to work at any job. She reported irritation and inflammation from handling newsprint, throat irritation and lung impairment because of smoke from wood furnaces, eye irritation, and other symptoms. MCS is linked with reports of acute sense of unpleasant smells, called cacosmia, loss of sense of smell, or anosmia, acute discomfort and irritation, and depression (1,2,7,8). The victim usually attributes the symptoms to an encounter with an unfamiliar smell or irritation, which the victim associates with exposure to a chemical ingredient in a household or office product (1,5). Because the quantities of chemicals are small, toxicologists cannot calculate dose-response relationships (9,10). Controlled studies are nearly impossible to design and conduct. The offensive chemicals include solvents such as
Received 27 July 1995 Accepted 10 April 1996
303
304 benzene, toluene and hexane, alcohols, aldehydes and ketones, which are 'inert' components of office, household products, and pesticides. The offensive chemicals are ingredients in cleaning products, new clothing, new carpets, vehicle exhaust, cosmetics, laser printers, moth balls, pesticides, paper, paints, perfume, gas stove emissions, and new particle board and plywood, among others (1,5,11,12). They may be found in mixtures with other inert ingredients, heavy metals from dyes or pesticides, and carbon monoxide or oxides of nitrogen in air pollution (1,9,10). The composition of these mixtures cannot be detected by analytical or sensory means (1). These offensive substances are individually and collectively referred to as 'multiple chemical sensitivity inducing agents,' or MCSIAs, in the context of this paper. As it is currently defined, MCS is unlike any other disease or syndrome in that the symptoms 'spread' to other MCSIAs and organs in addition to the MCSIAs that initially sensitize, and the organs that are initially sensitized. The scientific theories discussed here are neurological, physiological, and immunological in nature.
Criteria of multiple chemical sensitivities Ashford and Miller (1) have defined the elements of chemical sensitivity as follows: 1. symptoms involving many systems or every system simultaneously, and always involving central nervous system (CNS) symptoms such as fatigue, mood changes, memory and concentration difficulties; 2. different symptoms and severity in different individuals, even among those experiencing the same exposure; 3. induction or sensitization in an initial phase, involving pesticides, solvents and combustion products primarily; 4. triggering of the damage caused by sensitization, by lower levels of exposure than the initial exposures; 5. spreading of sensitivity to other chemical substances, which may or may not be similar; 6. food, alcohol, and medication intolerance in many patients. The Cullen case definition focuses on symptoms (9,10). This definition recites the multisystem effect, spreading between chemicals and systems, applicability of many diagnostic tests, acquisition from environmental sources, low triggering doses of MCSIAs and the failure of any one test to explain the result. The Cullen case definition is more appropriate to scientific research than the clinical setting (9,10).
MEDICAL HYPOTHESES
Staudenmayer (13) and Simon (14) concluded that MCS is psychological in origin. There is an overlap of more than fifty percent of MCS patients with patients who have been clinically diagnosed with anxiety, depression, or psychosomatic disorder (3). Clinical ecologists and specialists in environmental medicine recognize that immunological, neurological, and physiological symptoms of MCS have psychological components (2,4,15). But behavioral treatment of MCS is exhausting for victims, and may cause iatrogenic illness. Sensitization to MCSIAs may be genetic, infectious, or neurological (4,12). The trigger may be a neurological reflex mechanism, a stimulus to emotional memory, or a conditioned response to olfactory stimuli.
Immunological theories There is no agreement on mechanisms of immune system effect in MCS patients (1,5,9). Some studies report a general immune suppression (1,4). Some experiments reported only suppression of B cells (1), which may result from injury to B lymphocytes or T helper cells (16). The finding of exclusive B cell suppression tends to support the viewpoint that MCS involves delayed hypersensitivity caused by activated T helper cells (1,5,17). Rea (18), Vojdani (19), and Kipen et al (68) independently measured total T and B cells, T cell ratio (CD4+/CD8+), mitogenesis, and immunoglobulins of MCS patients. Vojdani (19) and Kipen et al (68) also measured natural killer (NK) cells and NK activities. The only controls were measurements of a healthy population. The results of these studies were summarized by Ashford and Miller (1) and Meggs (17). The B cell counts in MCS patients tend to be lower than in the population controls, and the mitogenesis response is decreased (1,5,17). The T cell ratio tends to be lower than in the population. However, the decreased measurements in MCS patients are within 20% of the population measurements. Ashford and Miller (1) interpreted these results as indicators of increased cytotoxic T cell activity. Baseline measurements of immune system function were not obtained in these studies, which compared population averages to MCS patient averages (11,16, 17). B and T cell subsets were not measured. These studies were ecologic in nature. In a cross-sectional study of exposure to MCSIAs, the decreases in immune system activities of humans and animals were slight (20). It proves that the capacity of a normal individual's immune system is greater than injury done by MCSIAs (20). In some studies of human response to ozone and nitrogen dioxide, which are combustion products of
305
MULTIPLE CHEMICAL SENSITIVITIES
MCSIAs and also ambient air pollutants, the results indicated immunosuppression (21). In other studies of these pollutants, the results demonstrated nonspecific immune system activation as measured by polymorphonuclear (PMN) cells and alveolar macrophages (22,23). Nonspecific activation is caused by increased permeability of the lung epithelia to antigens, tissue damage, and attraction of immunoglobulin E (IgE) to the site, followed by degranulation of mast cells and release of histamines, or atopic susceptibility (1,22, 24). The tissue damage could be caused by reactive oxygen species (ROS) or free radicals (23,25). Tolerance causes unpredictable changes in immune system markers. Naive T cells are rendered tolerant by B cells presenting antigen, but memory T cells are activated by the same B cells (26). Fuchs and Matzinger (26) tested this hypothesis in C57BL/10 mice and proved that naive T cells are rendered tolerant to spleen cells from the male mouse because the B cell cannot provide a costimulatory signal. The memory T cell does not require a costimulatory signal and is activated. Also, as hypothesized by Fuchs and Matzinger, there may be tolerance in the 'low concentration zone' where antigen is presented only by B cells, activation in the moderate zone where antigen is presented by B cells and professional antigenpresenting cells, and tolerance in the high concentration zone where excess antigen is presented by B cells. If the Fuchs and Matzinger hypothesis of tolerance is true, it may explain why some MCS patients have low B cell counts and experience delayed hypersensitivity at the same time. A molecular experiment might test the theory of induced tolerance of naive T cells in MCS patients (26). Such a study should examine the behavior of T cell subsets of delayed hypersensitivity cells (Tdth), suppressor inducer cells (CD4+), subsets of T memory (CD45 +) and B memory cells, and mitogenesis (27-29). The investigator may identify the chemicals to which MCS study patients are exposed, in order to validate controls. Based on prior experiments with exposure to MCSIAs in cell cultures, laboratory animals, and people, there are many alternative explanations of immune response in MCS. For example, in animals exposure to dimethylbenzanthracene (DMBA) suppressed antibody (Ig) production, T cell cytotoxicity, and NK cell activity (30). DMBA is a polynuclear aromatic hydrocarbon (PAH). The mechanism was destruction of T helper cells, but the Tdth subset was not measured. In experiments with ozone in vitro, Becker (21) found that lymphocytes produce less Ig in response to T cell dependent mitogen, but response to the polyclonal B cell activator is the same. This experiment may prove that ozone does suppress the specific immune response, if concentrations are high
enough. Given the results of the other experiments with air pollution, it seems unlikely that ozone destroys the T helper cell or mutates its DNA. It is more likely that ozone damages the cell membrane. Diaz-Sanchez et al (31) measured responses to persons exposed to PAHs in clinically administered nasal lavages. The subjects were Los Angeles residents who are chronically exposed to PAHs in particulate smog. Saxon et al (31, and personal communication) found that IgE production was increased in subjects as compared with controls. It seems unlikely that these PAHs are any less mutagenic than DMBA. However, at the concentrations used in this study, they were not mutagenic, because Saxon measured increases in IgE mRNA. Saxon's results may be explained as an adjuvant effect (16,32), or as a tolerance mechanism (5,26,33). In normal persons, coping promotes immune response after an initial suppression caused by chemical exposure or stress (24). In a study of chronic stress in people living near the Three Mile Island nuclear power plant which was concluded six years after the radiation accident, the population had the same number of T helper cells as the comparison group, more neutrophils, and fewer B cells and T suppressor cells (11). Active coping did not occur, and the downward trend in cell proliferation reversed with time. The number of suppressor cells was less than normal. The immune response to a latent virus was normal at all times. Vojdani et al (19) reported the discovery of T cell epitopes for various chemicals such as benzene and toluene, and a slight increase in autoantibodies. Autoimmunity is a more appropriate hypothesis for MCS than the possibility of a T cell receptor for MCSIAs (16,34). Molecular mimicry in this situation would involve similarity of the amino acid sequence of a virus envelope and a career molecule for MCSIAs as haptens, and a cross-reaction between antibodies to the virus and the carrier molecule (34,35). MCS is not clinically recognized by immunologists. Jewett demonstrated that persons with food allergies cannot distinguish between a placebo and the putative allergen in double-blind provocationneutralization (36). Wolf (37) has suggested that MCS diagnosis should be confirmed with a blind provocation test of hypersensitivity.
Neurological theories
Kindling, time-dependent sensitization, and pharmacology Most biological processes cause a habituating, or tolerant, response - i.e. one that diminishes in
306 response to repeated stimuli. MCS involves a sensitization response that is enhanced by repeated exposures. MCSIAs probably breach the blood-brain barrier through the olfactory nerve, and directly cause sensitization of the CNS (1,2). The seizure-like activity which results is known as kindling. Kindling is associated with epilepsy in laboratory animals. Animal models of kindling were first developed to explain the nonhomologous process of bipolar depression in humans. MCSIAs also cause time-dependent sensitization (TDS), which is a deterioration in stability of central nervous system, endocrine, and behavioral markers without kindling (9,15,38,39). Kindling and TDS may result from a single exposure to MCSIAs (39,40). Repeated exposures to MCSIAs can cause spontaneous seizures (39,40). The kindling apparently causes deterioration of long-term potentiation, which is a mechanism of efficient learning and memory (2,15,39). Kindling may cause sensory irritation and deficits in learning and memory. Bell proved that pesticides and other MCSIAs cause kindling in laboratory animals (2,15). Other investigators have obtained similar results with pharmaceuticals and MCSIAs (38-40). The kindling occurs in the limbic structures which are sites of short-term memory and association functions, chiefly the amygdala and hippocampus. Glutamateresponsive neurons are common in the limbic system, and glutamate levels correlate with kindling (39). Many neuropeptides of hypothalamic and extrahypothalamic origin are found in the hippocampus. Kindling may explain the spreading of MCS, because kindling 'spreads' between target organs and between chemicals. MCS almost always involves variations in neuroendocrine parameters. Bell has suggested that MCS spreads between chemicals and target organs because of corticotropin releasing hormone (CRH) release from the hypothalamus during kindling (15). The pathways of CRH, and its functions in the limbic system, are very complex. Bell has postulated an interaction of excitotoxicity and CRH action, which is based on the evidence of CRH interaction with cytokines, neurotransmitters, neuropeptides, and hormones (see below). Speculation about pharmacologic models of MCS has focused on glutamate receptors in the hippocampus, kindling, and excitotoxicity. When norepinephrine is released in the central nervous system during stress and binds to hippocampal neurons, it reduces the hyperpolarization afterdischarge of potassium ion (K+) (24,41). Norepinephrine potentiates glutamate neurotransmitter activity as a result (42). When toxic chemicals are bound to the GABAa receptor, the response to glutamate is disinhibited
MEDICAL HYPOTHESES
(24,43). Glutamate causes degranulation of mast cells (24). Degranulations of mast cells, mucus producing cells, and mononuclear cells in the lungs cause delayed hypersensitivity (24). A pharmacologic model should account for the 'masking' phase of MCS, which is biphasic. The cyclodiene pesticides dieldrin and lindane, among others, bind tightly to the picrotoxin site of GABAa receptors in CFS patients (43). GABA-induced chloride influx is inhibited (43), and the victim suffers convulsions. Doses which are too low to cause convulsions are anxiogenic, which probably results from nonspecific binding to benzodiazepine receptors (44). The conclusive effect corresponds to the sensitization phase of MCS, and the anxiogenic effect corresponds to the masking phase. The blockage of benzodiazepine receptors by pharmacologic agents which do not bind tightly to the picrotoxin site of the GABAa receptor causes a potentiation of glutamate at n-methyl-d-aspartate (NMDA) receptors, which causes an increase in long-term potentiation, or excitotoxicity if glutamate concentrations are excessive (24,39,43). When benzodiazepine receptors are nonspecifically blocked by some MCSIAs, defensive behavior is precluded, and coping strategies are activated (43,45). The coping strategy may mask the sensitization and the excitotoxicity. Although cyclodiene pesticides bind to the picrotoxin site of the GABAa receptor in CFS patients, CFS patients do not manifest substantial cognitive deficits (3,43). Whether this is the result of exposure to fewer MCSIAs or the greater adaptive ability of CFS patients is unknown. The benzodiazepine receptor is not implicated in cognitive activity. In MCS patients, exposure to organophosphate pesticides damages cholinergic neurotransmitter input to the dentate gyrus of the hippocampus, where cholinergic activity is modulated by GABA (32). The damage to cholinergic input affects adrenergic neurotransmitter input to the dentate gyrus, and learning and memory deficits may result (46). Furthermore, if dopamine receptors are stimulated, this neurotransmitter causes other behavioral symptoms of MCS such as lack of spontaneity and stereotypical behavior (40). Neuromodulation is the result of allosteric binding of neurotransmitters to receptors (41). The GABAa receptor has an allosteric steroid receptor (43). The binding of picryl chloride at the GABAa receptor alters the balance between Type 1 and Type 2 corticosteroid receptors (43). The ultimate physiological effect is unknown, but it may be important to MCS. The effect of diet cannot be neglected. Fatty acids and cholesterol in the diet are anti-inflammatory
307
MULTIPLE CHEMICAL SENSITIVITIES
because the body responds with diminished production of B 4 leukotrienes and interleukin-1 (IL-1) (42). Fatty acids and cholesterol in the diet reduce lymphocyte and neutrophil (PMN) responses as measured by mitogenesis (42). However, excitotoxicity causes degranulation of mast cells and inflammation (24). Fatty acids and cholesterol depress glucocorticoid formation, which abates the suppression of excitotoxicity (42).
factor (elF-2) (52). It is stimulated by interferon. The phosphorylated eIF-2 blocks the exchange of GDP for GTP, replication of the virus, and may suppress tumors (52,53). Concurrently, PKR phosphorylates the MAD-3 protein of the I-r~B family of inhibitors of NF-lcB (53). The phosphorylated protein disassociates from NF-~B, which enhances transcription in the cell nucleus. PKR activity may be relevant to MCS because NF-~B causes inflammation in response to ROS and free radicals (54).
Signal transduction Some mechanisms for signal transduction are relevant to MCS neurotoxicity. The first such theory is the signal transduction response to tumor necrosis factor-~ (TNF-c0, IL-1, and ultraviolet (UV) light, which are all stimulated by environmental stress (16). The protein kinase JNK is activated by phosphorylation of Thr and Tyr by a dual-specificity mitogenesis-activated protein (MAP) kinase, JKK. INK phosphorylates the transcription factor c-Jun and the protein kinase p38 (47). Activity of the Fos-Jun heterodimer is linked to long-term potentiation, and synaptic plasticity (40). Kandel has studied the mechanism of long-term potentiation in the hippocampal neuron, in response to an influx of glutamate (48). In long-term learning, postsynaptic cells are depolarized, the n-methyl-daspartate (NMDA) receptor is activated, calcium ion (Ca 2+) influx into the cell follows, adenylate cyclase and cyclic adenosine monophosphate (cAMP) are stimulated, and the catalytic subunit of protein kinase A (PKA) translocates to the nucleus. In the nucleus, PKA activates a MAP kinase and the CREB transcription factor, which enhances production of messenger ribonucleic acid (mRNA) and protein synthesis for neuron synapses. Kandel's group have confirmed the results of these cellular studies with knockout mice experiments (49). The knockout mice cannot synthesize protein for the synapses, and cannot alter their behavior in response to appropriate stimuli. For these molecular mechanisms to cause MCS, glutamate levels must first be upregulated. If there is a defect in the CRH response to stress as hypothesized for MCS patients (2), this defect could cause increased glutamate levels. Furthermore, both glucose and glutamine are energy sources for lymphocytes (42). If glutamine is diverted to synthesis of glutamate, a shortage of glutamine for lymphocyte metabolism may result. Acetate is a metabolic product of some MCSIAs (50), and a substrate for glutamate synthesis (51). Protein kinase R (PKR) is a RNA-activated kinase which inhibits protein synthesis by phosphorylating a subunit of the essential polypeptide chain initiation
Markers MCS patients often report sensations of anosmia, cacosmia and dysosmia (2,7,21). Anosmia is a loss of the sense of smell; and cacosmia is perceiving a smell as unpleasant which most people perceive as pleasant (7). Dysosmia is partial anosmia. Cacosmia is associated with memory loss, and advanced age (2,8). MCSIAs which are slightly soluble in water, i.e. organic solvents, may be concentrated in the olfactory mucus relative to ambient concentrations (7,46). MCSIAs are also metabolized to olfactory stimulants and irritants by enzymes that are abundant in olfactory epithelium, especially cytochrome P450 (46). There are millions of olfactory neurons, which are continually replaced. Allelic exclusion contributes to the genetic diversity (7,55). Exposures to some MCSIAs damage olfactory epithelia (56-58). Subsequently, function and morphology of the epithelia regenerate, but there is residual damage. Hurtt et al suggested that the residual damage could be the reason for specific anosmia in humans (58). However, Hurtt et al concluded that if olfactory tissue is only partially destroyed, neuropsychological testing is meaningless. Therefore olfactory response is not a wholly reliable marker of MCS. Brain scans have provided evidence of excitotoxicity, in abnormal single positron emission computerized tomography (SPECT) and positron emission tomography (PET) scans, and electroencephalograms (EEG) and evoked olfactory potentials (EOP) of MCS patients (9,39,59). The subjects manifested MCS symptoms and intermediate markers of excitotoxicity (59). The brain mapping techniques are the most reliable clinical markers of neurotoxicity so far. MCSIAs may stimulate the trigeminal nerve endings which are located in the olfactory passages, and cause a conditioned response in long-term memory in the hippocampus (2,15). A conditioned response which involves cytokines, interferon- a, and neurotransmitters has been studied in laboratory animals (46). The results of these studies may define markers of MCS in the future.
308 Other neurotoxicities
The bidirectional communication between lymphocytes and the hypothalamic and pituitary axis (HPA) is well established. Lymphocytes have receptors for hormones, neurotransmitters, and lymphokines which are produced by the HPA or peripheral cells (29,46,60-62). Autocrine and paracrine interactions are implicated in these receptor-mediated events. In nonstressful situations, the cortisol which is produced in the adrenal gland has negative feedback on the pituitary gland, which decreases norepinephrine production and increases corticotropin (ACTH) production (24). ACTH suppresses the immune system (28,61). Cortisol suppresses the immune system, and causes negative feedback on ACTH production in the pituitary (24,46,60-62). When there is stress, norepinephrine increases in the circulation and so does ACTH (46,60-62). Coping reinstates negative feedback (28,42,46). Corticotropin-releasing hormone (CRH) release from the hypothalamus stimulates the production of neuropeptides, chiefly substance P, which irritates the sensory organs (38). CRH release in the central nervous system is associated with norepinephrine release solely in stressful situations (42,50). CRH stimulates the release of catecholamines and opioid neuropeptides (24,42). In stressful situations, timedependent sensitization is blocked by a CRH antagonist (38). A CRH antagonist causes excitotoxic-like symptoms involving irreversible impairment of cognitive functions in laboratory animals (24). MCS and CFS patients report increased symptoms under stress (4,8,9,14). Since norepinephrine potentiates the effect of glutamate neurotransmitter in the central nervous system, this result is expected. Epinephrine stimulates the production of lactate (50); and lactate is implicated in panic syndrome. However, neither lactate, norepinephrine, nor epinephrine is validated as a marker of chronic stress. In CFS patients, reduced pituitary and adrenal feedback of cortisol to the hypothalamus cause low CRH levels and low cortisol (3). There are no published results for MCS patients, but the measured results are similar. CFS and MCS patients may both suffer from a defect in the ability of CRH to enhance negative feedback of cortisol, and the stress may become chronic in this manner. ROS and free radicals have an additive effect. Some MCSIAs cause free-radical damage in MCS patients (9,18), which may potentiate the excitotoxicity of MCSIAs (42,63,64). ROS and free radicals cause hyperreactive airways (25,63). Investigators are examining the potentiating effect of nitric oxide on glutamate toxicity (64).
MEDICAL HYPOTHESES
A mixture of toluene and benzene is immunosuppressive, but benzene causes more suppression than the mixture (33,65). The same mixture has additive effect in the CNS and causes depression (66). The opposite effects may be caused by differential effects of ROS and free radicals in the nervous and immune systems, especially with regard to interaction with excitotoxins and glucocorticoids (25,46). Excitotoxicity is linked to significant changes in neuropeptide activity including substance P (24). Substance P is stored in vesicles, which are located near or in excitatory neurons. The MCSIAs ozone and nitrogen dioxide damage the airway epithelium and expose non-adrenergic, non-cholinergic (NANC) sensory nerve endings (9,67). The nerve endings release substance P, which causes bronchoconstriction and hyperreactivity in animals and humans (9,24,67). Substance P stimulates mast cells, eosinophils and macrophages, and causes inflammation of the lung. When cholinergic and adrenergic neurotransmission pathways are blocked by pharmaceutical drugs, allergens and cigarette smoke cause pulmonary resistance (63). Both inhibitory NANC neurons and excitatory NANC neurons are found in the bronchial epithelia (56). Excitatory NANC neurons cause irritant-induced asthma and adult respiratory distress syndrome (ARDS) in research studies (56,63,67). Stimulation of excitatory NANC neurons by substance P, or malfunction of inhibitory NANC neurons by an unknown mechanism, could cause asthma and respiratory distress in MCS patients. Opioid neuropeptides such as 13-endorphin and the enkephalins counteract the effects of substance P in vitro (46). Apparently opioids act as neuromodulators, because low doses of exogenously administered opioids cause kindling-like convulsions in vivo (15). The opioid neuromodulation may explain the paradoxical effects of organic solvents. Exposure to organic solvents in the moderate range of 250-500 parts per million (p.p.m.) causes giddiness and hyperactivity, and an apparent increase in locomotor activity (65). Very-high-level exposure causes depression and narcosis, because of decreased neurotransmitter activity (65). Activated macrophages produce the inflammatory cytokine IL-1 (25,46,60,61). IL-1 enhances opioid receptor binding in the brain; and the interaction with IL-1 demonstrates the neuromodulatory effect of opioids (46,61). IL-1 stimulates production of CRH in the hypothalamus. Other considerations Eosinophilia promotes formation of free radicals (42). Eosinophils damage epithelia, and are recruited by
309
MULTIPLE CHEMICAL SENSITIVITIES
histamine mediators released by mast cells (24,42). However, eosinophils are rarely monitored in MCS patients, and when these cells are monitored there is no eosinophilia. Researchers have long speculated that the 'body burden' of stored fat containing chlorinated pesticides and solvents causes the classic symptoms of MCS, when stress mobilizes the pollutants from the stored fat and causes their release to the circulation (18). An inadequate diet and mobilization of chemicals from stored fat may explain simultaneous 'masking' and spreading of MCS symptoms and immune suppression, because supplies of zinc, iron and copper are also very important to an activated immune system (64). Inadequate diet and mobilization of fat stores do not explain simultaneous MCS symptoms and immune suppression. However, immune suppression is not confirmed as a universal symptom of MCS patients, and it is possible that the mobilization of pollutants overwhelms the metabolism. Certainly, some pollutants such as ethanol induce the cytochrome P450 system (66). Xenobiotic-induced disease states alter peripheral immune cell responses to the neurotransmitter acetylcholine (46). The 'environmental' diseases sometimes enhance cytokine production in immune cells, including IL-1 and IL-2; and upregulation of these cytokines may cause mental depression (46). It may be possible to demonstrate a conditioned response to stress in MCS patients, involving interactions of cytokines and neurotransmitters (24,42,46). In in vitro experiments, stress and exposure to toxic chemicals cause a downshift of natural killer cell activity which is associated with the passage of interferon-beta (IFN-[3) across the blood-brain barrier to the CNS (46). This is a conditioned response in some animal models.
3.
4.
5.
6.
7.
Research hypotheses The following is a list of likely research hypotheses for future experiments. These hypotheses are derived from the discussion in the paper. 1. Free-radical concentrations may be measured in epithelial ceils derived from MCS patients after exposure to MCSIA. Correlations of free-radical concentrations, glutamate levels, and neutrophil and eosinophil activities might be evaluated. Freeradical concentrations may be measured using scavenger agents. Results could be compared for CFS and MCS patients. It would be instructive to compare results for MCS and CFS patients. 2. The bidirectional communication between the immune system and nervous systems may be
8.
9.
investigated in MCS patients. Correlations of the CD4+/CD8 + cell ratio with activity of c~ and [3 adrenergic receptors and norepinephrine levels may be evaluated in vitro after exposure to MCSIA. The effect of various cytokines on the T cell ratio could be demonstrated. Markers of immune system effect can be improved with measurements of the effects of MCSIAs, including irritants and mutagens, using standard immune cell experiments. An experiment could also be performed on adrenalectomized mice to determine the immune suppression which is caused by MCSIA exposure. MCS symptoms may be correlated with routes of exposure and differential impacts on the subsets of T helper cells, including Tdtu and suppressor inducer cells, and adhesion cells. The experiment should include separate measurements of naive T cell and memory T cell activities. A variation of this experiment might involve observations under mild escapable and inescapable stress. The regulation of genes which cause inflammation, chiefly NF-k[3, may be studied in epithelial cells in vitro. Correlations of the activity of this gene with cyclic adenosine monophosphate (cAMP) and norepinephrine levels can be evaluated, using [3 receptor blockers. The impact of the tumor suppressor gene PKR may be measured in mice with a 'knocked-out' gene. The mice can be challenged with antigen in the presence of pollutants. Immune response to latent viruses, such as the herpes simplex virus used in the Three Mile Island experiment, may be measured in vitro. If there is response, it may demonstrate integration of the virus into the host genome. Molecular mimicry of viruses and the genes of target organs can be evaluated. Kindling and TDS for various pesticides and MCSIAs which have been previously analyzed in laboratory animals may be studied in the same laboratory animals to determine the effect of metabolism by cytochrome P-450 in the olfactory epithelia. The impact of health status on TDS and kindling should be measured. Brainwave activity of laboratory animals may be measured with PET and MRI scans after exposure to MCSIA. The brainwave activities may be correlated with levels of neurotransmitters in the brain. Markers which are used clinically for purposes of diagnosing other conditions, such as phenylalanine for depression, bronchoalveolar lavage for lung impairment, and other amino acids should be investigated in MCS patients for correlations with symptoms.
310
Conclusion Many interesting explanations for MCS and chemical-induced toxicity in general have been advanced. The theories of MCS as explained in this paper, are currently undergoing formulation and refinement. The author hopes that this paper may make a contribution to the understanding of MCS, and that the suggestions for future research will provide inspiration to scientists who are interested in this subject.
Acknowledgments I would like to acknowledge my faculty advisor, Dr Michael D. Collins of the UCLA School of Public Health for generous advice.
References 1. Ashford N, Miller C. Chemical Sensitivity: Low Exposures, High Stakes. Van Nostrand Reinhold, 1992. 2. Bell I. Neuropsychiatric aspects of sensitivity to low-level chemicals: a neural sensitization model. Toxicol Industr Health 1994; 10(4-5): 277-312. 3. Buchwald D, Garrity D. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med 1994; 154(18): 2049-2053. 4. Heuser G. Diagnostic Markers of Multiple Chemical Sensitivity, Addendum to Biologic Markers in Immunotoxicology 117-38. Washington, DC: National Research Council, 1992. 5. Hileman B. Multiple chemical sensitivity. Chem & Engr News 1991; 69(29): 26-42. 6. Wilson C. Chemical sensitivity - - one victim's perspective. Toxicol Industr Health 1994; 10(4-5): 319-322. 7. Dory R L. Olfaction and multiple chemical sensitivity. Toxicol Industr Health 1994; 10(4-5): 359-368. 8. Shnsterman D, Sheedy J E. Occupational and environmental disorders of the special senses. Occup Med 1992; 7(3): 515-542. 9. Sparks P J e t al. Multiple chemical sensitivity syndrome: a clinical perspective, I: case definition, theories of pathogenesis and research needs. J Occup Med 1994; 36(7): 718-730. 10. Sparks P J e t al. Multiple chemical sensitivity syndrome: a clinical perspective, II: evaluation, diagnostic testing, treatment and social considerations. J Occup Med 1994; 36(7): 731-737. 11. McKinnon W, Weisse C S, Reynolds C P, Bowles C A, Baum A. Chronic stress, leukocyte subpopulations, and humoral response to latent viruses. Health Psychol 1989; 8(4): 389-402. 12. Samet J, ed. Environment controls and lung disease, report of the ATS Workshop on Environment Controls and Lung Disease. Am Rev Respir Disease 1990; 142(4): 915-939. 13. Staudenmayer H, Selner M E, Selner J C. Adult sequelae of childhood abuse presenting as environmental illness. Ann Allergy 1993; 71(6): 538-546. 14. Simon G E, Daniell W, Stockbridge H, Claypoole K, Rosenstock L. Immunologic, psychological and neurophysiological factors in multiple chemical sensitivity. Ann Intern Med 1993; 19(2): 97-103. 15. Bell I R, Schwartz G E, Peterson J M, Amend D, Stini W A. Possible time-dependent sensitization to xenobiotics: selfreported illness from chemical odors, foods, and opiate drugs in an older adult population. Arch Env Health 1993; 48(13): 315.
MEDICAL HYPOTHESES
16. McGrath K G, Zeiss C R, Patterson R. Allergic reactions to industrial chemicals. Clin Immunol Rev 1983; 2(1): 1-58. 17. Meggs W J. Multiple chemical sensitivities and the immune system. Toxicol Industr Health 1992; 8(5): 203-214. 18. Rea W. Chemical Sensitivity, Vol. 1. Boca Raton: CRC Press, 1992. 19. Vojdani A, Ghoneum M, Brautbar N. Immune alteration associated with exposure to toxic chemicals. Toxicol Industr Health 1992; 8(5): 239-257. 20. Hong R. Effect of environmental toxins on lymphocyte function: studies in rhesus and man. Ann Allergy 1991; 66(6): 474-480. 21. Becker S. Ozone effects on human immunoglobulin production. J Toxicol Env Health 1990; 34(3): 353-366. 22. Devlin R B. Exposure of humans to ambient levels of ozone. Am J Respiratory Cell Mol Biol 1991; 4(1): 72-81. 23. Friedman M E, Madden M C, Samet J M, Koren H S. Effects of ozone exposure on lipid metabolism in human alveolar macrophages. Env Health Perspectives 1992; 97: 95-101. 24. Djuric V J, Bienenstock J. Learned sensitivity. Ann Allergy 1993; 71(1): 5-14. 25. Whitacre C M, Cathlart M K. Oxygen free radical generation and regulation of proliferative activity of human mononuclear cells responding to different mitogens. Cell Immunol 1992; 144(2): 287-295. 26. Fuchs E J, Matzinger P. B cells tuna off virgin but not memory T cells. Science 1992; 258(5085): 1156-1159. 27. Munson A E, McLay J A, Cat W. Approaches to immunotoxicology studies with emphasis on chemical-induced immunomodulation. Ann Allergy 1991; 66(6): 505-518. 28. Sheridan J F et al. Restraint stress differentially affects antiviral cellular and humoral immune responses in mice. J Neuroimmunol 1991; 31(3): 245-255. 29. Whitacre C M. Immunology: a state of the art lecture. Ann NY Acad Sci 1990; 594: 1-16. 30. Dean J H, Ward E C, Murray M H, Lauer L D, House R V. Mechanisms of dimethylbenzanthracene-induced immunotoxicity. Clin Physiol Biochem 1985; 3(2-3): 98-110. 31. Diaz-Sanchez D, Dotson A R, Takenaka H, Saxon A. Diesel exhaust particles induce local IgE production in vivo and alter the pattern of IgE messenger RNA isoforms. J Clin Invest 1994; 94(4): 1417-1425. 32. Davenas E, Beneveniste J e t al. Human basophil degranulation triggered by very dilute antiserum against IgE. Nature 1988; 333(6176): 816. 33. Hsieh G C, Sharma R P, Parker R D. Hypothaiamic-pituitaryadrenocortical axis activity and immune function after oral exposure to benzene and toluene. Immunopharmacology 1991; 21(1): 23-32. 34. Gleichmann E, Kimber I, Purchase I F. Immunotoxicology: suppressive and stimulatory effects of drugs and environmental chemicals on the immune system. Arch Toxicol 1989; 63(4): 257-273. 35. Merrill J E, Jonakait G M. Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease. FASEB J 1995; 9(8): 611-618. 36. Jewett D L et al. A double-blind study of symptom provocation to determine food sensitivity. N Engl J Med 1990; 323(7): 429-433. 37. Wolf C. Multiple chemical sensitivities - - is there a scientific basis? Int Arch Occup Env Health 1994; 66(4): 213-216. 38. Antelman S M. Time-dependent sensitization in animals: a possible model of multiple chemical sensitivity in humans. Toxicol Industr Health 1994; 10(4-5): 335-342. 39. Gilbert M E. The phenomenology of limbic kindling. Toxicol Industr Health 1994; 10(4-5): 343-358. 40. Weiss S. Caveats in the use of the kindling model of affective disorder. Toxicol Industr Health 1994; 10(4-5): 421-448.
MULTIPLE CHEMICAL SENSITIVITIES 41. Bloom F E. Neurotransmitters: past, present and future directions. FASEB J 1988; 2(1): 32-41. 42. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993; 329(17): 1246-1253. 43. Corrigan F M, MacDonald S, Brown A, Armstrong K, Armstrong E M. Neurasthenic fatigue, chemical sensitivity and GABAa receptor toxins. Meal Hypotheses 1994; 43(4): 195-200. 44. Leslie J C, Liam T, Shephard R A. Conditioned suppression and the effect of pentobarbital with picrotoxin, flumazenil and R05-3663. Psychol Rec 1995; 45(2): 299-307. 45. Kalin N H. The nenrobiology of fear. Sci Am 1993; 268(5): 94-101. 46. Fuchs B, Sanders V M. The role of brain-immune interactions in immunotoxicology. Crit Rev Toxicol 1994; 24(2): 151-176. 47. Davis R J. MAPKs: new JNK expands the group. Trends Biochem Sci 1994; 19(11): 470-473. 48. Kandei E, Abel T. Neuropeptides, adenyl cyclase, and memory storage. Science 1995; 268(5212): 825-826. 49. Grant S G N e t al. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 1992; 258(5090): 1903-1910. 50. Iatropoulos M. Endocrine considerations in toxicologic pathology. Exp Toxicol Pathol 1993-4; 45(7): 391-410. 51. Ishizaka S, Kikuchi E, Higashino T, Kinoshita K, Tjujii T. Effects of acetate on the immune system of mice. Int J Immunopharm 1990; 12(1): 135-143. 52. Wek R C. eIF-2 Kinases: regulators of general and genespecific translation initiation. Trends Biochem Sci 1994; 19(11): 491-496. 53. Clemens M. Suppression with a difference. Nature 1992; 360(6401): 210-211. 54. Xia C, Hu J, Ketterer B, Taylor J B. The organization of the human GSTP-1 gene promoter and its response to retinoic acid and cellular redox status. Biochem J 1996; 313 (Part 1): 155-161. 55. Lancet D. Exclusive receptors. Nature 1994; 372(6504): 321-322. 56. Barnes P J. Neural mechanisms in asthma. Br Med Bull 1992; 48(1): 149-168.
311 57. Cone J A e t al. Persistent respiratory health effects after a metam sodium pesticide spill. Chest 1994; 106(2): 500-508. 58. Hunt M E , Thomas D A, Working P K, Monticello T M, Morgan K T. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: pathology, cell kinetics, and olfactory function. Toxicol Appl Pharmacol 1988; 94(2): 311-328. 59. Heuser G, Mena I, Atamos F. NeuroSPECT findings in patients exposed to neurotoxic chemicals. Toxicol Industr Health t994; 10(4-5): 561-572. 60. Black P H. Psychoneuroimmnnology: brain and immunity. Sci & Med (Sci Am) 1995; 2(6): 16-25. 61. Black P H. Central nervous system-immune system interactions: psychoneuroendocrinology of stress and its immune consequences. Antimicrob Agents Chemother 1994; 38(1): 1-6. 62. Black P H. Central nervous system-immune system interactions: effect and immunomodulatory consequences of immune system mediators on the brain. Antimicrob Agents Chemother 1994; 38(1): 7-12. 63. Nishiwaka M, Ikeda H, Fukuda T, Suzuki S, Okubo T. Acute exposure to cigarette smoke induces airway hyperresponsiveness without airway inflammation in guinea pigs. Am Rev Resp Disease 1990; 142(1): 177-183. 64. Serog P. Clinical status of nutritional origin involving immune deficiency. Food Addit Contain 1990; 7(Suppl. 1): $87-$93. 65. Hsieh G C et al. Subclinical effects of groundwater contamination - - 1I: alteration of brain monoamine neurotransmitters by benzene in CD-1 mice. Arch Env Contamination Toxicol 1988; 17(6): 799-805. 66. Lang L. Strange brew: assessing risk of chemical mixtures. Env Health Perspectives 1995; 103(2): 142-145. 67. Stretton D. Nonadrenergic non-cholinergic neural control of the airways. Clin Exp Pharmacol Physiol 1991; 18(10): 675-684. 68. Kipen H e t al. Immunologic evaluation of chemically sensitive patients. Toxicol Industr Health 1992; 8(5): 125-135. 69. Holt P G e t al. Defence against allergic sensitization in the healthy lung: the role of inhalation tolerance. Clin Exp Allergy 1989; 19(3): 255-262.