hardin,' - emerge...

Individual Differences in Neural Sensitizationand the Role of Context in Illness fromLow-level Environmental Chemical ExposuresIris R. Bell,1'2'5 Gary E. Schwartz,1'2'3 Carol M. Baldwin,2'4Elizabeth E. Hardin,' Nancy G. Klimas,67 John P. Kline,2Roberto Patarca,6 and Zhi-Ying Song2Departments of 1Psychiatry, 2Psychology, and 3Neurology, and 4Divisionof Respiratory Sciences, University of Arizona, Tucson, Arizona;5Department of Psychiatry, Tucson Veterans Affairs Medical Center,Tucson, Arizona, 6Department of Medicine (Immunology), Universityof Miami School of Medicine, Miami, Florida; 7Miami Veterans AffairsMedical Center, Miami, Florida

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlinesthe concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, anddiscusses experimental design implications of the model for exposure-related research. Neuralsensitization is the progressive amplification of responsivity by the passage of time betweenrepeated, intermittent exposures. Initiation of sensitization may require single toxic or multiplesubtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxiclevels. Thus, neural sensitization could account for the ability of low levels of environmentalchemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitizationinclude limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) andtime-dependent sensitization of behavioral, neurochemical, immunological, and endocrinologicalvariables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part formany of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration inperception making familiar objects or people seem unfamiliar or unreal) is a common MCSsymptom and has been linked with limbic dysfunction in clinical neuroscience research.Sensitization is distinct from, but interactive with, other neurobiological learning and memoryprocesses such as conditioning and habituation (compare adaptation or tolerance). In previousstudies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation)have often been considered in isolation from one another. To design more appropriate chemicalexposure studies, it may be important to integrate the various theoretical models and empiricalapproaches to MCS with the larger scientific literature on individual differences in these potentiallyinteractive 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 outlines the possible relationshipsbetween the olfactory-limbic system andneural sensitization model for multiplechemical sensitivity (MCS) (1) and certainexposure-related symptoms; and discussespotential interactions between individual

differences in neural sensitization, con-ditioning (context), and habituation (tol-erance; adaptation) that might affectexperimental design in MCS studies. Wedescribe the model briefly, using data andconclusions from our laboratory studies on

This paper is based on a presentation at the Conference on Experimental Approaches to Chemical Sensitivityheld 20-22 September 1995 in Princeton, New Jersey. Manuscript received at EHP 6 March 1996; manuscriptaccepted 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 1 16A, Tucson, AZ 85723. Telephone: (520) 792-1450, ext 5127. Fax: (520) 629-4632. E-mail: [email protected]

Abbreviations used: ADHD, attention-deficit/hyperactivity disorder; ASI, Anxiety Sensitivity Index; CNS,central nervous system; CS, conditioned stimulus; DA, dopamine; EEG, electroencephalogram; MCS, multiplechemical sensitivity; SCL-90-R, Symptom Checklist 90 (revised); TDS, time-dependent sensitization; TLE,temporal lobe epilepsy; UCS, unconditioned stimulus.

chemically sensitive human subjects to illus-trate certain points. Research on chemicallyintolerant subjects thus far indicates thatthey a) exhibit bidirectional variabilityaround an unstable set point (2) or failureof habituation over time; b) report certainlifetime patterns of medical (3-5) and psy-chiatric (6-9) conditions that require expla-nation in any MCS model; c) present morecomplex clinical phenomenology thanchemical avoidance behaviors alone (3,4).

Multiple Chemical SensitivityClinical Observations ThatRequire ExplanationIt is essential to note that the clinicalobservations summarized below represent amixture of anecdotal and controlled datafrom the published literature, with relevantcitations. Much of the specific epidemio-logic and laboratory study evidence neededto support particular points is not avail-able. At the same time, these concepts rep-resent a core of clinical information thatrequires articulation in order to designproper studies for testing the assumptionsand various mechanistic hypotheses forMCS. MCS is a chronic, polysymptomaticcondition. Affected individuals reportrecurrent flares of illness when exposed tolow levels of environmental chemicals (e.g.,pesticides, solvents), common foods (e.g.,milk, chocolate, wheat, sugar), multipledrugs, and other ingestants (e.g., alcohol,chlorinated water) (10). Women represent70 to 80% of the affected population (10).The illness process involves two steps: initi-ation and elicitation (10). Many (11), butnot all (12), MCS patients report an iden-tifiable, acute, or subacute exposure eventin which they inhaled, absorbed, oringested toxic levels of a particular chemi-cal agent. Typically, the initiating sub-stances are pesticides or solvents (4,5).Patients report recovery from the moreclassical, substance-specific toxic effects,followed by a deterioration in overallhealth over a period of weeks to months.Subsequent eliciting agents are numerousand diverse in chemical structures, butoften similar in their adverse effects.Triggers can include previously toleratedlevels of pesticides, perfumes, deodorizers,gasoline, paint, new carpet, fresh news-print, or traffic exhaust, as well as foods,drugs, and alcohol (4). Patients report theability to return to a relatively normal base-line if they avoid exposures to incitingagents (13). Some investigators postulate

Environmental Health Perspectives * Vol 105, Supplement 2 * March 1997 457

BELL ET AL.

that adaptation to chronic exposuresdampens the degree of reactivity to expo-sures under certain circumstances (5).They suggest that this adaptation necessi-tates removal from chronic exposures priorto acute sensitivity testing to avoid type IIerror (5,10).

Individual reactions to many chemicallyunrelated substances include cognitive diffi-culties with concentration and memory,neuromuscular, gastrointestinal, affective,musculoskeletal, respiratory, and cardiacdysfunctions, and fatigue (3,4,11,14).Miller and Mitzel (4) found that cognitivesymptoms of MCS such as slowed think-ing, memory problems, and concentrationdifficulty are among the most severe dys-functions, whereas feelings of unreality/spaciness and lightheadedness are amongthe most frequent features of the condition(15). Symptoms of a given adverse reactioncan begin within minutes or be delayed forup to 24 hr after a given exposure or inges-tion (16). Once triggered, reactions lastfrom minutes to several days, even if theexposure is terminated promptly (16).Different phases of the same reaction caninvolve activated states such as insomnia,anxiety, or irritability, and deactivated statessuch as sleepiness or depression in the sameperson, i.e., bidirectionality (5,10,16).MCS patients also report increased lifetimerates of physician-diagnosed rhinitis, sinusi-tis, menstrual disorders, irritable bowel,arthritis, migraine headaches, breast orovarian cysts, depression, and panic disor-der (3,6-8). MCS patients usually showmarked avoidant behaviors toward inhaledchemicals (for which onset of adverse reac-tions is within minutes), but often extremecravings for foods such as sweets (for whichonset of adverse reactions is delayed byhours) (5). MCS reactions include somaticmanifestations as well, involving autonomicdysfunction or inflammation at multiplesites (17-19).A recent study indicated that MCS

patients make an average of 23 health careprovider visits per year (20). This poorlyunderstood condition is costly in termsof worker's compensation, personal injurylitigation, and health care utilization.Although definitive population-basedstudies have not been published, the esti-mated prevalence of MCS ranges from 0.2to 4% of the general population (21,22).Morrow et al. (23,24) found that 60% ofsolvent-exposed industrial workers mani-fested symptoms of illness from chemicalodor. Bell et al. (21,25-27) demonstratedless severe self-reported chemical odor

intolerance in 15 to 30% of young adultcollege student (mean ages 18-19 years)and active retired community elderly(mean ages 68-76 years) samples. In con-trast with MCS populations (3,4,6), nei-ther the college students nor the elderlyindividuals with chemical odor intoleranceworked in the chemical or associatedindustries or perceived themselves as dis-abled by chemical-related illness at thetime of the study.

MCS is a complex condition that, onceestablished, defies traditional dose-responserelationships of toxicology. That is, inMCS, low doses trigger large responses.The symptom of illness from low-levelchemical odors is common in populationsnot motivated by secondary gain in termsof worker's compensation or disabilityclaims (22). The manifestations of adversereactions are multiple and individualized,and often include involvement of thecentral nervous system (CNS) (3,4).

Olfactory-Limbic and NeuralSensitization ModelThe olfactory-limbic and neural sensi-tization model proposes that individual dif-ferences in reactivity to environmentalsubstances in MCS derive from neurobio-logically based sensitization of the olfactory,limbic, mesolimbic, and related pathways ofthe CNS (1,28). The nose is a direct path-way into the limbic system both for neuralsignals (odor-olfactory and irritant-trigem-inal) (29,30) and for transport of manymolecules (31,32). Among the sensory sys-tems, only the olfactory system lacks ablood-brain barrier (29,30). The olfactorybulb, amygdala, and hippocampus areinterconnected parts of a phylogeneticallyolder portion of the brain that is particu-larly vulnerable to sensitization processes(33,34). Repeated intermittent exposuresto a given stimulus lead to progressivelyincreased levels of responsivity over time inthose structures (1,33,34). Sensitizationthen persists without reexposures for longperiods of time. As a result, Stewart andBadiani (35) refer to sensitization as a basicform of learning and memory. Indeed,drugs that can interfere with the neurobiol-ogy of learning, such as excitatory aminoacid antagonists or protein synthesisinhibitors, can also block acquisition of sen-sitization (36-38). The limbic region par-ticipates in regulation of a broad range ofpsychological and physiological functions,including anger, fear, learning and mem-ory, reproduction, eating, drinking, auto-nomic activity, and pain (39-41). Limbic

dysfunction could lead to polysymptomaticconditions involving neurobehavioral andsomatic manifestations (1).

KindlingKindling is the prototypical sensitizationprocess, in which a low-level electrical orchemical stimulus that initially had little orno effect on behavior eventually elicits per-sistent vulnerability to electrographic andbehavioral seizures after daily repetition for10 to 14 days (42). Kindling is consideredan animal model for temporal lobe epilepsy(TLE) in humans. Full kindling is unlikelyto provide an explanation for most MCScases, as increased rates of TLE per se andother clinically obvious seizure disorders arenot present in the majority ofMCS patients.However, partial kindling to a point shortof seizures produces persistent changes inelectrical firing patterns and in aggressiveand social behaviors of animals (43). Manyenvironmental chemicals, especially pesti-cides (44-46) and the solvent toluene(34), induce chemical kindling or partialkindling, or facilitate electrical kindling ofthe amygdala in animals. Rossi (42) hasrecently published a detailed examinationof the basic neurobiology issues in kindlingas a model for MCS.

No studies have yet directly examinedMCS patients for electrophysiological evi-dence of partial kindling, TLE (complexpartial seizures), simple partial seizures, orsubclinical seizure disorders. In view of theassociation of high rates of polycystic ovarydisease in women with TLE (47), a historyof ovarian cysts (3) could suggest focalamygdala or hypothalamic dysfunctionresulting in reproductive hormone dysreg-ulation in MCS patients. Moreover, Bell etal. have shown that young adults (48) andmiddle-aged women (49,50) with chemicalodor intolerance have higher scores thando their chemically tolerant peers on theMcLean Limbic Symptom Checklist. Thisscale is based on self-ratings of the fre-quency of ictal symptoms of TLE such assomatic, sensory, behavioral, and memorydysfunctions (51).

Several different studies have shown thatMCS patients have an inordinately high rateof past or comorbid depression and panicdisorder (6-8), conditions also associatedwith limbic system dysfunction. Notably, asubset of panic disorder patients with symp-toms of derealization and other sensory dis-tortions actually exhibit electrophysiologicalpatterns of simple partial seizures (e.g., uni-lateral delta-theta slowing over temporalregions) during attacks in supermarkets and

Environmental Health Perspectives * Vol 105, Supplement 2 * March 1997458

NEURAL SENSITIZATION AND LOW-LEVEL CHEMICALS

malls monitored with ambulatory electro-encephalogram (EEG) (52). In addition,nasal inhalation of an olfactory stimulusodor (sweet orange in propylene glycol) tostimulate the temporolimbic regions insuch panic disorder patients who were notexperiencing an attack elicited increases inEEG delta (slow wave, 2-4 Hz) activity notseen in panic patients without the derealiza-tion symptom or in normals (53). In otherwords, panic patients with temporolimbicsymptoms of derealization and other sen-sory distortions show epileptiform EEGalterations with ambulatory monitoringand/or odor inhalation. By analogy, odor-elicited temporal lobe dysfunction couldexplain in part the derealization symptomin MCS patients. However, such odor reac-tivity may be present only under conditionsof sensitization, not necessarily in a single,isolated test (28).

Time-dependentSensitizationAnimal studies have permitted systematicexamination of the phenomenology andmechanisms of time-dependent sensitiza-tion (TDS). Among various efferents, theamygdala sends excitatory input to thenucleus accumbens of the dopaminergicmesolimbic pathway (54). As a result, theamygdala can modulate (but is not neces-sarily required for) another nonkindlingtype of neural sensitization known as time-dependent sensitization (55). TDS is theprogressive increase in responsivity of agiven outcome measure with the passage oftime between the initial and later exposuresto a pharmacological or nonpharmacologi-cal stimulus or stressor (56). Agents thatdiffer widely in their structural and phar-macological properties can all induce,elicit, and/or modulate TDS (56-60),including stimulants, p opioids, glucocor-ticoids, tranquilizers, antidepressants,immunosuppressants, pertussis or choleratoxins, and neuromodulators such as sub-stance P, and volatile organic agents suchas ethanol (61), toluene (62), or formalde-hyde (63). Sensitizable outcomes may bebehavioral, neurochemical, immune, orendocrine. Outcomes may also be bidirec-tional (increases or decreases), dependingon the individual's past history with thesensitizing or cross-sensitizing agent(61,64). Convulsions are not necessarilyinvolved in TDS, and drugs such asanticonvulsants that block kindling do notprevent TDS-type effects (65).

Previous research suggests that thepatterns of response to exposures under

different time factors can distinguish sensi-tization from other neurobehavioralprocesses such as classical conditioning orhabituation (Table 1). For example, theinitial response to a given stimulus may beof magnitude 1+ in sensitization andhabituation. The magnitude of the initialresponse to a conditioned stimulus (CS)would be 0 in conditioning. Namely, onlythe unconditioned stimulus (UCS) canelicit the 1+ biological response, and theUCS would not be retested; the initialresponse to the unconditioned stimulusthat is paired with the UCS is 0. Thus, theresponse magnitude upon initiation coulddistinguish conditioning from sensitiza-tion and habituation. However, if thestimulus is given again soon after the ini-tial exposure, the response is dampened to0 in habituation, while it remains 1+ insensitization and grows from 0 to 1+ tothe CS in conditioning. Thus, rapid repe-tition of a stimulus could distinguishhabituation from the other two phenom-ena. After the passage of time, themagnitude of the response in sensitization(amplification of responsivity by passage oftime) would be 3+, whereas it would be 1+in habituation (restoration of responsivityby passage of time without reexposures).In contrast, the magnitude of the responseto the CS in conditioning would diminishbecause of a lack of repeated pairings withthe UCS or even oppose that of the UCS(66). Thus, delay between reexposures to astimulus could distinguish sensitizationfrom the other two phenomena.

Sensitization is further complicated bythe potential for interaction with condi-tioning processes in a context-dependentmanner (Table 2). That is, if the initiatingand eliciting stimuli are given in the samephysical environment, then it is possible toelicit the sensitized response only in thatsame, familiar environment (35,67).Testing for elicitation of sensitization in anenvironment different from the one wherethe process was initiated, (e.g., testing in alaboratory when the illness is reported atwork) will elicit only a baseline magnitudeof response. In this circumstance, the sensi-tization may still be present, but notobservable. By analogy, the degree of nov-elty of environments, in ascending orderwould be home, work, MCS laboratory(Table 2). In context-dependent sensitiza-tion, it is preferable to both initiate andelicit sensitization in the laboratory; other-wise, testing in a novel site after initiationin a familiar setting (4) could fail to elicitsensitization when it is actually present.

These context-related concepts derivefrom previous animal research. Badiani etal. (67) studied the interaction of stimu-lant drugs with the environment (homeversus novel cage for both initiating andtest exposures) and with individual differ-ences in behavior over a 1-week protocol.They found that it was possible to induce agreater degree of sensitization of rotationalbehavior if both initiating and test expo-sures were given in a novel cage, ratherthan if the exposures were all given in thehome cage. This design parallels previous

Table 1. Predicted size of response compared with unexposed controls to a repeated stimulus in sensitization,conditioning, and habituation, based on time since the individual's previous exposure.

(a) Reactivity to initial (b) Effect of time (c) Effect of more time,exposure in environment with rapid reexposure without rapid reexposure

Sensitizationa + + +++

Conditioning 0 (CR) + (CR) 0 (CR)Habituationa + 0 +

CR, conditioned response to a previously neutral, biologically inactive stimulus (conditioned stimulus [CS]) initiallypaired with a biologically active stimulus (unconditioned stimulus [UCS], which initially causes a positive uncondi-tioned response [UCRI). NOTE: All three processes can occur in the same individual for a given exposure. The netobserved effect will be a complex summation of their respective underlying effects. Within this table, assume theresponses represent outcomes for each process by itself. Sensitization proceeds by the passage of time after theinitial exposure without further reexposures. Retests produce progressively larger responses. Conditioning pro-ceeds by repeated pairing of UCS and CS starting with the initial exposure until CS alone elicits CR. Repeatedretests of CS without repairing with UCS over time extinguishes CR and produces progressively smaller responses.Habituation proceeds by continuous exposure or frequent repetition of exposures. Retests produce progressivelysmaller responses. "If repeated chemical exposures were to induce both sensitization and habituation together invarying degrees, then the net observed response might be modified from the simple examples in the table above.That is, under time pattern b, the net response would be present but dampened [i.e., 0 to 1/2 +, masked oradapted by concomitant habituation (5,10)]. Under time pattern c, the net response would be present and ampli-fied as in the sensitized state [i.e., +++, unmasked or de-adapted by the removal of habituation (5,10)]. If repeatedchemical exposures were to induce both sensitization and conditioning together, then the net observed responsemight be one of the scenarios shown in Table 2.


BELL ET AL.

Table 2. Predicted size of context-dependent response to a given chemical during challenge testing by interactionwith environmental factors, from the sensitization model for MCS without dishabituation or de-adaptation (35,67).Assume a baseline level of chronic symptoms at 1+.

Response vs baselineLive in Sensitize to chemical Test chemical Predicted size after Predicted size afterenvironment in environment in environment test chemical placebo

[i] Home Home Home 2+ 1+[ii] Home Work Work 3+ 1-2+[iii] Home MCS laboratory MCS laboratory 4+ 2+[iv] Home Home MCS laboratory 1-2+ 1-2+[v] Home Work MCS laboratory 1-2+ 1-2+

The degree of novelty of a given environment (scenarios ii and iii should heighten sensitization if the initiation andelicitation both occur there. A novel environment should dampen the size of an elicited response if the initiation isremoved from the environment in which testing for elicitation occurs (scenarios iv and v). Research scenario iii ismore likely than iv or v to distinguish active from placebo. However, fluctuations in baseline symptomatologywithout dishabituation make it difficult to differentiate active from placebo in all scenarios, especially ivand v.

human studies in which investigators gavethe sensitizing exposures (session a) andtest exposures (session b) in the same novellaboratory setting (49,50,68). Badiani etal. (67) also demonstrated that the ani-mals with lower responses to amphetamineduring the first session exhibited thegreater sensitization of rotational behaviorafter 7 days when sensitizing and test doseswere given in a novel environment. Incontrast, animals with higher responses toamphetamine during session a exhibitedhabituation, not sensitization, of rotationalbehavior after 7 days when all sensitizingand test doses were given in the homeenvironment. Similarly, Sorg et al. (63)noted differential sensitization to formal-dehyde as a function of initial locomotorresponsivity to a novel environment.

Sensitization is not merely a type ofconditioning. Animal studies have demon-strated the ability to extinguish the condi-tioned responsivity to the experimentalcontext by giving sham exposures (e.g.,saline injections) without eliminating thesensitized response to the actual substance(e.g., a drug) in the same setting (69). Re-exposure to the original stimulus immedi-ately elicits the sensitized response despiteextinction of the context responsivity. It isalso possible to initiate and elicit sensitiza-tion in a context-independent manner (70).For this type of sensitization, the environ-ment in which the initiating stimulus isgiven varies among exposures; wheneverthe stimulus is readminstered, the laterresponses will be amplified, i.e., sensitized,regardless of the environment in whichthe reexposures occur. One animal studysuggests that animals with the greatestbehavioral reactivity to novelty are moreprone to develop both stimulant drug self-administration (71) and context-dependent

rather than context-independent sensitiza-tion. These findings raise the possibility ofstudying analogous individual differencesin human subjects to explain why oneperson progresses into severe MCS andanother does not.A sensitization model also accomodates

possible comorbid psychiatric disordersand stress factors in MCS. TDS is a neuro-biological process, but drugs and stress(physical or psychological) can cross-sensi-tize (initiate TDS) when tested later intime (56,72,73). Hormones present in thephysiological stress response (compare withglucocorticoids) may be required for initia-tion of TDS to stress (74), though notnecessarily to pharmacologic agents (75).Estrogens favor acceleration of the develop-ment ofTDS in animals (76), and femalessensitize more readily than do males (77).TDS is emerging as a leading model forvarious chronic recurrent disorders such asdrug craving and addiction (78), posttrau-matic stress disorder (79), bipolar disorder(80), recurrent unipolar depression (80),and eating disorders such as bulimia (56).Various investigators have linked MCSwith all of these disorders with the notableexception of drug abuse (81). Antelman(57) and Bell (28,81) have reviewed theextensive overlaps between MCS and TDS.Bell et al. have found increased histories ofdrug problems in the families of chemicallyintolerant young adults (48) and of alcoholproblems in the families of chemicallyintolerant middle-aged adults (50). Thus,the genetic vulnerability to substance abuseproblems may be present, but may not beexpressed as such in MCS patients.

Another leading MCS symptom isconcentration difficulty (4,15). This symp-tom may have neurophysiological correlatesin the slow EEG frequency, absolute theta

(4-8 Hz). That is, normal young adultstrained to produce increased amounts ofEEG theta perform more poorly on tests ofvigilance than do controls trained to pro-duce decreased amounts of theta (82). Wehave studied temporoparietal theta activityamong young adults with depressed affectby using nasal inhalation of filtered roomair immediately following a series of low-level chemical exposures (n-butanol, galax-olide, propylene glycol) and other tasks.Under those conditions, we found increasedtheta at rest after the chemicals within thechemically intolerant subset compared withthose who reported tolerating chemicals(83). Notably, children with attention-deficit/hyperactivity disorder (ADHD) alsoexhibit increased levels of EEG thetaactivity, especially during cognitive tasks(84,85), which researchers have linkedwith feelings of unreality (84). In a recentsurvey, chemically intolerant young menreported an increased rate of childhoodADHD diagnoses (86). The dopaminergicpathways involved in TDS have also beenimplicated in ADHD (87).

Bell et al. also have evidence for TDSof the endogenous opioid, plasma P-endor-phin (2), and of cardiovascular measures(88) over multiple laboratory sessionsinvolving foods and stress in older adultswith moderate levels of chemical odorintolerance. The endorphin levels of thechemically intolerant subjects were gener-ally elevated, but changed direction fromsession to session relative to those of thenormals. In addition, greater initial psycho-logical distress correlated with lower endor-phin levels later in the study for thechemically intolerant as contrasted withhigher endorphin levels under the sameconditions for the normals (2). The chemi-cally intolerant group also had waking dias-tolic blood pressures that were higher onthe second than on the first days in the lab-oratory, whereas the normals showed theopposite pattern (88). Despite this variabil-ity, averaged over six measurements, wakingblood pressures of the chemically intolerantelderly were higher overall than those oftheir normal peers. Bell et al. have foundincreased diastolic blood pressures and/orheart rate over time in two subsequent labo-ratory studies of chemically intolerant indi-viduals in which chemical exposures weregiven (49,50). Together, the data suggestinstability of certain physiological variablesbetween measurements and paradoxicalreversals in the direction of some stress-related responses for chemically intolerantindividuals over time. The findings are


NEURAL SENSMZATION AND LOW-LEVEL CHEMICALS

consistent with Antelman et al.'s (61,64)data on bidirectionality in TDS. Higherperipheral endorphin levels could lead tononimmunological release of histaminefrom mast cells (89). If so, endorphin couldaccount for some of the allergylike symp-toms such as rhinitis, breathing problems,or hives reported in MCS patients withoutatopy (3,4,90). Moreover, p opioids suchas [-endorphin can initiate TDS in animalstudies (58) and can modulate cardiovas-cular tone in human subjects (91).

The same group of chemically intoler-ant elderly described above also exhibitedobjective polysomnographic sleep patternssuch as decreased total sleep time, increasedwaking, and decreased rapid-eye movementsleep, despite only slightly elevated subjec-tive ratings of sleep disturbance comparedwith chemically tolerant controls (92).Milk, a commonly implicated food incitantin MCS (4), was associated with poorersleep than was soy beverage in the chemi-cally intolerant group. One of several possi-ble neurochemical bases for the arousedsleep pattern that would be consistent withTDS is increased dopamine activity and/orresponsivity (DA) (93), e.g., in mesolimbicpathways (94). Many but not all animalstudies of TDS have reported progressiveincreases in mesolimbic DA activity duringinduction of TDS (54,59). DA is also amajor neurotransmitter in the olfactorybulb for odor discrimination (94) and inthe hypothalamus for inhibition of thereproductive/stress hormone prolactin (95).

Plasma prolactin levels are accessibleindicators of CNS dopamine (95,96).That is, increased hypothalamic dopaminehas been shown to act as prolactin inhi-bitory factor, i.e., decreasing prolactin out-put into the blood. Prolactin is oftenelevated in cases of psychological or physi-ological stress (97). Consequently, serumprolactin could offer an objective correlateof sensitization and of stress responses. Aspart of a study of subsequent blood pres-sure sensitization (49), Bell et al. examinedbaseline 4 P.M. resting serum prolactinlevels (drawn upon study enrollment andassayed with a standard commercial kit) inmiddle-aged women with and without self-rated chemical odor intolerance. Data fromthe depressed and nondepressed controlswithout chemical intolerance were aver-aged in this analysis; the resulting twogroups (CI and non-CI) did not differ inmean levels of psychological distress (SCL-90-R Global Severity Index, p= 0.969).Sitting and standing blood pressures werethen taken without concomitant chemical

exposures at the beginning and end of twosessions, spaced one week apart. Duringeach session, blinded, placebo-controlledchemical exposures were given, using iden-tical procedures. Significantly more of thechemically intolerant women (8/10, 80%)exhibited increased sitting diastolic bloodpressure from week one to week two thandid the chemically tolerant women (4/17,24%) (Fisher's Exact Test, p = 0 .007).Furthermore, the chemically intolerantwomen who showed laboratory evidence ofblood pressure sensitization had lowerbaseline prolactin levels, in contrast withchemically tolerant women who did notsensitize blood pressure (when a singlehyperprolactinemic 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 activityin the hypothalamus; or decreased CNShypothalamic dopamine with heightenedDA receptor sensitivity in the pituitary ofthe chemically intolerant individuals. Thedirection of the group difference for pro-lactin levels is consistent with sensitizationof dopaminergic activity to a low-level ini-tiating stimulus (61), rather than sensitiza-tion to a simple stress response model forchemical intolerance (in which more stressshould lead to higher prolactin). However,in view of the variability of the (-endorphindata and one prolactin outlier, it will beessential to replicate and extend the bloodstudies to multiple measurements over dif-ferent days and different times of day, atrest, and after chemical exposures, in largersamples of subjects. Nonetheless, the dataoverall suggest a labile but generally acti-vated neurochemical internal milieu inchemically intolerant individuals that mayinvolve at least opioids and dopamine.Design Implications ofTime-dependent SensitizationSensitizable and PreviouslySensiized IndividualsFor present purposes, hypotheses that derivefrom a TDS model have major designimplications for future studies of exposure-related symptoms in MCS (81). First, animportant hypothesis is that a subset ofMCS patients may be highly sensitizableindividuals, not only to environmentalchemicals, but also to foods, drugs, otherenvironmental factors, and life stressors(2,21,27,81,88,98). This implies that envi-ronmental chemicals may be the initiating

stimulus for the sensitizing process andthat chemicals may act synergistically withother classes of stimuli to initiate MCS(21,73). For example, it may be difficultretrospectively to distinguish the sensitizingphysiological effects of an acute toxicchemical spill of a single agent from thesensitizing psychophysiological effectsof the associated stress response (e.g.,,B-endorphin, cortisol) (99). It may still bepossible to try prospective pharmacologicalagents (e.g., dopamine antagonists to blockcertain types ofTDS initiation) (35,59) ornonpharmacological interventions (e.g.,brief cognitive psychotherapy to minimizethe perceived stressfulness of the event) atthe time of emergency treatment in patientsexposed to a chemical spill, to determineif a given class of intervention might pre-vent the later development of MCS on aTDS basis.

In the laboratory, cross-sensitizationbetween pharmacologic and nonpharmaco-logic stimuli in TDS means that demon-strating current reactivity to psychologicalstressors such as placebo will not prove alack of reactivity to chemical stimuli, andvice versa. The initial question thenbecomes whether certain MCS patients aresensitized to multiple environmental fac-tors (98), rather than the dualistic questionof a toxogenic versus psychogenic etiologyfor MCS (100). It is also possible that dif-ferent subsets of MCS patients experiencedifferent types of initiation factors, i.e.,some may have had early life psychologicalor physical trauma without chemicals(21,49) whereas others may have undergoneonly an identifiable chemical exposure eventin mid-adulthood (12). Some chemicalexposure events such as a toxic spill couldinvoke both stress and chemical effects toinitiate TDS, perhaps via the physiologicalstress response pathways (72-75). Chemicaland stress responses may be dependent onsome of the same final common biologicalmechanisms for initiation or elicitation ofsensitization (72,73). A key factor in TDSmay be the experienced or perceived threatto the individual from the environment(101,102). Studies must be designed tomanipulate systematically not only chemicalexposure levels and awareness of chemicals,but also the perceived stressfulness of thesetting in which the chemical exposuresoccur (67,102).

Animal studies suggest that between-group (different groups receiving theactive and sham treatments) rather thanwithin-group/crossover (the same groupsreceiving the active and sham treatments


BELL ET AL.

in counterbalanced order) designs maybe optimal to differentiate the chemicaleffects from those of experimental stress(56, 69,71,101,102). The difficulty forwithin-subjects designs is that the sensitiz-ing effects of either an active or a shamexposure may change the subsequentresponsivity to the next test (sham oractive) in the same individual (56,61,64).For example, Badiani et al. (67) found amuch less intense but nonetheless increasedresponse to saline injections in animals thathad been pretreated with active stimulantdrug in a novel environment, when sensi-tizing and the test drug doses were all givenin a novel environment. However, thesaline effect was apparently conditioned tospecific circumstances. It was not presentfor saline when the pretreatment hadinvolved active drug in a home environ-ment, or saline in either home or novelenvironment. These latter observationsmay affect the interpretation of studiessuch as those of Staudenmayer et al. (103),who reported an unreliable pattern ofMCS patient symptom data in differentiat-ing chemical from sham challenges. Thewithin-subjects design and the pretesting ofmasking odors to determine initial lack ofreactivity in that study may have initiated asensitization process to the testing proce-dures or the masking odors in the MCSpatients. Consequently, subjects could havebeen reactive in a seemingly unreliablemanner to various test exposures whenthey were in fact sensitized to both activeand sham agents. This point is importantbecause of recent findings that mint odor,for instance, used repeatedly as a maskingodor in Staudenmayer's human MCSstudy (103), can initiate olfactory-limbicsensitization in animals (34). Similarly,examination of the study designs ofnonatopic adverse food reactions in MCSpatients suggests that a failure to appreciatethe implications of sensitization can lead towidely divergent experimental outcomes(15,26). Systematic designs to test for sen-sitization with awareness of its potentialinteractions with contextual conditioningand with adaptation are essential to avoidmethodological pitfalls in future MCSchemical and sham exposure studies.

Context-dependent andContext-independentSensitizationSecond, as discussed above, TDS candevelop in either context-dependent (con-ditioned) or context-independent ways(35,55,59,67,102). That is, varying the

setting in which the sensitizing substance isencountered will enable the individual toexhibit a sensitized response in any setting(context-independence). However, if thechemical exposure is usually paired withparticular environmental, nonchemicalcues (context-dependence), then single ses-sion studies in a novel laboratory situationmay miss a true effect. Studies have shownthat animals with established sensitizationwho receive the test agent in a new cagedifferent from the one in which the drugwas usually given during initiation of sensi-tization will not show a sensitized response.When returned to the original, drug-pairedsetting, sensitized animals will again exhibitheightened responsivity to the drug (35)(Table 2). Furthermore, in establishedcontext-dependent TDS, environmentalchemicals may not be the only elicitingstimulus for symptoms. Some degree ofheightened response may occur in animalsgiven saline in the cage previously pairedwith active drug (67). Consequently, theinherent stressfulness, familiarity, or nov-elty of the experimental setting and proce-dures themselves may play a substantialrole in the outcome of MCS studiesinvolving TDS (35,67,69,71,75,104).Both context-dependent and context-inde-pendent sensitization theoretically mightoccur in the same person. However, ani-mals prone to drug self-administration(71) may be particularly susceptible to thecontext-dependent form; whereas animalsnot prone to stimulant drug self-adminis-tration (compare with a large subset ofMCS patients) (63) may be particularlysusceptible to the context-independentform (71).

This argument implies that field studiesin familiar settings such as office, factory,shopping malls, car, and home environ-ments may be as important as laboratorystudies. In this manner, it may be possibleto detect sensitized responses to chemicalsthat would be obscured in acute testswithin a novel and often threatening labo-ratory setting. However, multiple test ses-sions over periods of days and weeks in thesame setting would also help avoid type IIerror by facilitating development and elici-tation of context-dependent sensitization tothe experimental procedures (67), even ifthe ability to elicit pre-existing sensitizationwere initially inhibited (35).

It is also possible to design studies todifferentiate conditioned from sensitizedresponse. For example, Stewart's group(69) extinguished the conditioned compo-nent of a heightened response with saline

injections by repeated reexposure ofthe animals to the previously drug-pairedenvironment until the size of the responsereturned to baseline. However, when theygave the drug again, the sensitized responseimmediately reappeared, suggesting thatextinction addressed only the context-dependent part of the process, not the sen-sitization itself. Certain investigators haveclaimed the ability to desensitize MCSpatients to chemicals by particular psycho-logical extinction procedures (103). Itwould be crucial to determine not only ifthe procedures are actually effective insome MCS patients, but also if suchextinction eliminates chemical sensitizationcompletely, or simply the conditioned elic-itation of adverse reactions in certain situa-tions (69,71). The long-term healthimplications of remaining sensitized, eventhough not exhibiting context-dependentsensitized reactions in some settings, areunexamined at this time.

Sensitization and theAdaptation HypothesisThe sensitization hypothesis is compatiblewith the MCS-derived adaptation hypothe-sis; that is, a long-standing precept in MCSis that the heightened reactivity andanother process, called masking or adapta-tion, can develop at the same time (5,10).The corollary hypothesis is that adaptationmay obscure the ability to detect sensitizedresponses during challenge tests (Tables 1,2). Complete removal from all adaptation-inducing exposures for 4 or more days isrequired prior to attempting definitive test-ing for true adverse reactions to chemicals(10). Simple environmental chambers areinsufficient, as subjects can remain in themfor only a few hours during a day, with lit-tle impact on the adaptation process (5,10).The practical and financial limitations ofdeveloping environmentally controlledunits for research have impeded progress intesting the adaptation hypothesis.

Historically, many neurobiologicalresearchers have noted that sensitizationand habituation (compare tolerance, adap-tation) are distinct but interactive processes(71,105,106). Post (106) pointed out thatcontinuous or frequent exposures to a givenstimulus favor development of tolerance,whereas intermittent exposures favor devel-opment of sensitization. Studies haveshown that sensitization and habituationare not opposite ends of the same process,but independent, concomitant processesthat can summate. Habituation added to anotherwise sensitized response could result in


NEURAL SENSMZATION AND LOW-LEVEL CHEMICALS

mutual cancellation of effects, i.e., anapparent lack of change over time (105).Moreover, habituation to the test environ-ment itself in an acute test of a substancecan interact with individual differences ininclination to drug self-administration toalter drug response (35,67,71). Animalstudies indicate that MCS patients (who donot tend to be drug abusers) might notshow their capacity for heightened reactiv-ity to a chemical during an initial, one-ses-sion test. Thus, the basic neuroscienceliterature supports the MCS contentionthat adaptation and cross-adaptation tochronic chemical exposures could obscureevidence of heightened reactivity (Table 1).Days, not hours, of withdrawal from thesensitizing substance are needed to be ableto elicit a heightened response in TDS(54,59,71). Individual differences inresponses to habituation to the total (chem-ical, physical, and psychosocial) environ-ment in which the substance is encounteredalso may alter the outcome of a givenchemical challenge (35,71,102,107,108).

Time Factors inExperimental ApproachesAvailable data indicate two primary waysto design human studies testing for height-ened reactivity to environmental chemicals:a) place patients in an environmentallycontrolled unit and remove them from allsources of the suspect chemicals and cross-sensitizing stimuli for a period of daysprior to challenge tests (10). This effec-tively removes habituation while providingoptimal time for emergence of sensitiza-tion; b) use inherently more versus lesssensitizable individuals and induce context-dependent sensitization to common chemi-cals in an initially novel laboratory settingover multiple sessions, separated by daysfrom one another (2,68,98). Such a proce-dure would make the heightened reactivityto an otherwise familiar and habituatedsubstance dependent upon the new settingin which it is encountered (67).

Design a relies largely on deadaptationto reveal pre-existing, context-independentsensitization. It is important to emphasizethat both sensitization and habituationare likely to contribute to the reportedpatterns of reactivity in MCS patients in anenvironmental control unit. (design a).That is, if adaptation to ambient exposuresoutside the unit were the only issue, thenremoving adaptation by avoidance for a

few days would restore not hyperreactiv-ity, but simply reactivity. Instead, clini-cians observed a marked hyperreactivity(10,16), matching that of a sensitizedresponse (35,102).

Design b relies largely on experimen-tally initiated, context-dependent (condi-tioned) sensitization. The individual mayor may not have had preexisting sensitiza-tion to the substance. The underlyingassumption is that the patient is inherentlymore sensitizable than a normal person.Design b takes advantage of the possibilityof inducing and then testing for sensitiza-tion by using the laboratory setting itself tomake the first exposure to the substancenovel and the later exposures familiar, i.e.,to foster context-dependent sensitization(Table 2). Newlin and Thomson (68) havealready demonstrated the feasibility ofdesign b in human subjects. They com-pared changes in autonomic nervous sys-tem responses to ingestion of alcohol onthree different days in sons of alcoholicsand sons of nonalcoholics (all of whomused alcohol socially and nonabusively).The outpatient sessions were spread over atwo-week period in the National Instituteof Drug Abuse laboratory. The sons ofalcoholics exhibited less ability to habituateand more capacity to sensitize the auto-nomic measures over sessions than did thecontrol subjects. They also tested for con-ditioned responses to the laboratory settingalone, without alcohol after the last session.Autonomic patterns reverted to baselinelevels in the absence of alcohol. Thus, acontext-dependent sensitization to alcoholwas observed in sons of alcoholics, inwhich the conditioned component reliedon concomitant exposure to the substanceand to the setting, not to the setting alone.

Our own preliminary polysomno-graphic, quantitative EEG, endorphin,and cardiovascular data suggest the feasi-bility of the multiple, identical-sessiondesign for MCS studies. This approachmay permit induction and elicitation ofsensitized responding in chemically intol-erant human subjects without necessitat-ing use of an environmentally controlledhospital unit. However, designs a and bfacilitate asking different types of ques-tions. For design a, the main question canbe whether the individual is currentlysensitive to a given substance. For designb, the main question can be whether theindividual is unusually sensitizable.

Another important methodologicalconsideration is that exposure levels mustbe intermittent and perhaps fluctuating,with breaks of hours and even days fromone exposure to the next, if sensitization isto develop (106). The constant levels ofchemicals used in many toxicology studiescould minimize sensitization and favor tol-erance. Real-world exposures in humanpopulations are generally intermittent andfluctuate over time. Previous investigatorshave treated inconsistencies in dose duringlaboratory studies as a potential proceduralflaw. On the contrary, the constancy andlack of interruptions in experimental dos-ing may help explain why tolerance hasbeen reported more often than sensitiza-tion in toxicology research., The majorethical consideration for this research inhumans is the need to limit the number ofrepeated exposures during the research pro-tocol. Kalivas et al. (59) point out that sen-sitization to a few scattered exposures istemporary and reversible, but massed dailyexposures for a week induce permanentsensitization in animals.

ConclusionsMCS is much more than behavioralavoidance of chemicals; explanations ofMCS must account for a broad range ofclinical observations (100). These obser-vations include low rates of drug use andabuse despite elevated levels of affectivedistress (28). The partial limbic kindlingand TDS model has a limited, but grow-ing, amount of empirical evidence inhumans (2,27,88,109) and in animals(34,44,45,62,63) to support its involve-ment in the multiple symptoms, phenom-enology, and medical/psychiatric picturesof MCS patients (81). In particular, thesensitization model suggests specificexperimental design considerations, with-out which one risks missing a true effect(type II error). Previous hypotheses forMCS involving sensitization, condition-ing, and adaptation have often been con-sidered in isolation from one another. Todesign more appropriate chemical expo-sure studies, it may be important to inte-grate the various theoretical models andempirical approaches to MCS with thelarger scientific literature on individualdifferences in these potentially interactivephenomena (35,59,67,69,71,105,106).


BELL ET AL.

REFERENCES

1. Bell IR, Miller CS, Schwartz GE. An olfactory-limbic model ofmultiple chemical sensitivity syndrome: possible relationshipsto kindling and affective spectrum disorders. Biol Psychiatry32:218-242 (1992).

2. Bell IR, Bootzin RR, Davis T, Hau V, Ritenbaugh C, JohnsonKA, Schwartz GE. Time-dependent sensitization of plasmabeta-endorphin in community elderly with self-reported envi-ronmental chemical odor intolerance. Biol Psychiatry40:134-143 (1996).

3. Bell IR, Peterson JM, Schwartz GE. Medical histories and psy-chological profiles of middle-aged women with and withoutself-reported illness from environmental chemicals. J ClinPsychiatry 56:151-160 (1995).

4. Miller CS, Mitzel HC. Chemical sensitivity attributed to pesti-cide exposure versus remodeling. Arch Environ Health50:119-129 (1995).

5. Miller CS. Chemical sensitivity: history and phenomenology.Toxicol Ind Health 10:253-276 (1994).

6. Simon GE, Katon WJ, Sparks PJ. Allergic to life: psychologicalfactors in environmental illness. Am J Psychiatry 147:901-906(1990).

7. Simon GE, Daniell W, Stockbridge H, Claypoole K,Rosenstock L. Immunologic, psychological, and neuropsycho-logical factors in multiple chemical sensitivity. A controlledstudy. Ann Int Med 19:97-103 (1993).

8. Black DW, Rathe A, Goldstein RB. Environmental illness. Acontrolled study of 26 subjects with "20th century disease."JAMA 264:3166-3170 (1990).

9. Fiedler N, Kipen H, DeLuca J, Kelly-McNeil K, Natelson B.Neuropsychology and psychology of MCS. Toxicol Ind Health10:545-554 (1994).

10. Ashford NA, Miller CS. Chemical Exposures. Low Levels andHigh Stakes. New York:Van Nostrand-Reinhold, 1991.

11. Cullen MR. The worker with multiple chemical sensitivities:an overview. Occup Med: State of the Art Reviews 2:655-662(1987).

12. Fiedler N, Kipen HM, DeLuca J, Kelly-McNeil K, Natelson B.A controlled comparison of multiple chemical sensitivities andchronic fatigue syndrome. Psychosom Med 58:38-49 (1996).

13. Ziem G. Multiple chemical sensitivity: treatment and followupwith avoidance and control of chemical exposures. Toxicol IndHealth 8:73-86 (1992).

14. Doty RL, Deems DA, Frye RE, Pelberg R, Shapiro A. Olfactorysensitivity, nasal resistance, and autonomic function in patientswith multiple chemical sensitivities. Arch Otolaryngol HeadNeck Surg 114:1422-1427 (1988).

15. Bell IR, Markley EJ, King DS, Asher S, Marby D, Kayne H,Greenwald M, Ogar DA, Margen S. Polysymptomatic syn-dromes and autonomic reactivity to nonfood stressors in indi-viduals with self-reported adverse food reactions. J Am CollNutrition 12:227-238 (1993).

16. Randolph TG. Specific adaptation. Ann Allergy 40:333-345(1978).

17. Meggs WJ. Neurogenic inflammation and sensitivity to environ-mental chemicals. Environ Health Perspect 101:234-238 (1993).

18. Meggs WJ. Neurogenic switching: a hypothesis for a mecha-nism for shifting the site of inflammation in allergy and chemi-cal sensitivity. Environ Health Perspect 103:54-56 (1995).

19. Ross GH. History and clinical presentation of the chemicallysensitive patient. Toxicol Ind Health 8:21-28 (1992).

20. Buchwald D, Garrity D: Comparison of patients with chronicfatigue syndrome, fibromyalgia, and multiple chemical sensitiv-ities. Arch Internal Med 154: 2049-2053 (1994).

21. Bell IR, Schwartz GE, Amend D, Peterson JM, Stini WA.Sensitization to early life stress and response to chemical odorsin older adults. Biol Psychiatry 35:857-863 (1994).

22. Meggs WJ, Dunn KA, Bloch RM, Goodman PE, Davidoff AL.Prevalence and nature of allergy and chemical sensitivity in a

general population. Arch Environ Health 51:275-282 (1996).23. Ryan CM, Morrow LA, Hodgson M. Cacosmia and neurobe-

havioral dysfunction associated with occupational exposure tomixtures of organic solvents. Am J Psychiatry 145:1442-1445(1988).

24. Morrow LA, Ryan CM, Hodgson MJ, Robin N. Alterations incognitive and psychological functioning after organic solventexposure. J Occup Med 32:444-450 (1990).

25. Bell IR, Schwartz GE, Peterson JM, Amend D. Self-reportedillness from chemical odors in young adults without clinicalsyndromes or occupational exposures. Arch Environ Health48:6-13 (1993).

26. Bell IR, Schwartz GE, Peterson JM, Amend D. Symptom andpersonality profiles of young adults from a college student pop-ulation with self-reported illness from foods and chemicals. JAm Coll Nutrition 12:693-702 (1993).

27. Bell IR, Schwartz GE, Peterson JM, Amend D, Stini WA.Possible time-dependent sensitization to xenobiotics: self-reportedillness from chemical odors, foods, and opiate drugs in an olderadult population. Arch Environ Health 48:315-327 (1993).

28. Bell IR. Neuropsychiatric aspects of sensitivity to low levelchemicals: a neural sensitization model. Toxicol Ind Health10:277-312 (1994).

29. Doty RL, ed. Handbook of Olfaction and Gustation. NewYork:Marcel Dekker, 1995.

30. Stevens DA, O'Connell RJ. Enhanced sensitivity toandrostenone following regular exposure to pemenone.Chemical Senses 20:413-419 (1995).

31. Shipley MT. Transport of molecules from nose to brain:transneuronal anterograde and retrograde labeling in the ratolfactory system by wheat germ agglutinin-horseradish peroxi-dase applied to the nasal epithelium. Brain Res Bull15:129-142 (1985).

32. Ghantous H, Dencker L, Gabrielsson J, Danielsson BRG,Bergman K. Accumulation and turnover of metabolites oftoluene and xylene in nasal mucosa and olfactory bulb in themouse. Pharmacol Toxicol 66:87-92 (1990).

33. Joy RM. Mode of action of lindane, dieldrin, and related insec-ticides in the central nervous system. Neurobehav ToxicolTeratol 4:813-823 (1982).

34. Kay LM. Support for the kindling hypothesis in multiplechemical sensitivity syndrome (MCSS) induction. SocNeuroscience 22:1825 (1996).

35. Stewart J, Badiani A. Tolerance and sensitization to the behav-ioral effects of drugs. Behav Pharmacol 4:289-312 (1993).

36. Gilbert ME, Mack CM. The NMDA blocker, MK-801, sup-presses long-term potentiation, kindling, and kindling-inducedpotentiation of the perforant path in the unanesthetized rat.Brain Res 519:89-96 (1990).

37. Stewart J, Druhan JP. Development of both conditioning andsensitization of the behavioral activating effects of amphetamineis blocked by the non-competitive NMDA receptor antagonist,MK-801. Psychopharmacology 110:125-132 (1993).

38. Karler R, Finnegan KT, Calder LD. Blockade of behavioralsensitization to cocaine and amphetamine by inhibitors of pro-tein synthesis. Brain Res 603:19-24 (1993).

39. Davis M. The role of the amygdala in fear and anxiety. AnnuRev Neurosci 15:353-375 (1992).

40. Mesulam MM. Principles of Behavioral Neurology.Philadelphia:FA Davis, 1985.

41. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution ofcentral neuroplasticity to pathological pain: review of clinicaland experimental evidence. Pain 52:259-285 (1993).

42. Rossi J. Sensitization induced by kindling and kindling-relatedphenomena as a model for multiple chemical sensitivity.Toxicol 111:87-100 (1996).

43. Adamec RE. Does kindling model anything clinically relevant?Biol Psychiatry 27:249-279 (1990).

464 Environmental Health Perspectives - Vol 105, Supplement 2 * March 1997

NEURAL SENSmZAnON AND LOW-LEVEL CHEMICALS

44. Gilbert, ME. Repeated exposure to lindane leads to behavioralsensitization and facilitates electrical kindling. NeurotoxicolTeratatol 17:131-141 (1995).

45. Gilbert ME. A characterization of chemical kindling with thepesticide endosulfan. Neurotoxicol Teratol 14:151-158(1992).

46. Gilbert ME. Neurotoxicants and limbic kindling. In: TheVulnerable Brain and Environmental Risks. Vol 1:Malnutrition and Hazard Assessment (Isaacson RL, Jensen KF,eds). New York:Plenum Press, 1992;173-193.

47. Herzog AG, Seibel MM, Schomer D, Vaitukaitis J, GeschwindN. Temporal lobe epilepsy: an extrahypothalamic pathogenesisfor polycystic ovarian syndrome? Neurology 34:1389-1393(1984).

48. Bell IR, Hardin EE, Baldwin CM, Schwartz GE. Increased lim-bic system symptomatology and sensitizability of young adultswith chemical and noise sensitivities. Environ Res 70:84-97(1995).

49. Bell IR, Baldwin CM, Russek LG, Schwartz GE, Hardin EE.Unpublished data.

50. Bell IR, Bootzin RR, Schwartz GE, Szarek MJ, DiCenso DR,Baldwin CM. Unpublished data.

51. Teicher MH, Glod CA, Surey J, Swett C. Early childhoodabuse and limbic system ratings in adult psychiatric outpa-tients. J Neuropsychiatry Clin Neurosci 5:301-306 (1993).

52. Weilberg JB, Schacter S, Worth J, Pollack MH, Sachs GS, IvesJR, Schomer DL. EEG abnormalities in patients with atypicalpanic attacks. J Clin Psychiatry 56:358-362 (1995).

53. Locatelli M, Bellodi L, Perna G, Scarone S. EEG power modi-fications in panic disorder during a temporolimbic activationtask: relationships with temporal lobe clinical symptomatology.J Neuropsychiatry Clin Neurosci 5:409-414 (1993).

54. Sorg BA, Hooks MS, Kalivas PW. Neuroanatomy and neuro-chemical mechanisms of time-dependent sensitization. ToxicolInd Health 19:369-386 (1994).

55. Alesdatter JE, Kalivas PW. Involvement of N-methyl-D-aspar-tate receptor stimulation in the ventral tegmental area andamygdala in behavioral sensitization to cocaine. J PharmacolExp Ther 267:486-495 (1993).

56. Antelman SM. Time-dependent sensitization as the corner-stone for a new approach to pharmacotherapy: drugs as for-eign/stressful stimuli. Drug Devel Res 14:1-30 (1988).

57. Antelman SM. Time-dependent sensitization in animals: a pos-sible model of multiple chemical sensitivity in humans. ToxicolInd Health 10:335-342 (1994).

58. Kalivas PW, Stewart J. Dopamine transmission in the initiationand expression of drug- and stress-induced sensitization ofmotor activity. Brain Res Rev 16:223-244 (1991).

59. Kalivas PW, Sorg BA, Hooks MS. The pharmacology andneural circuitry of sensitization to psychostimulants. BehavPharmacol 4:315-334 (1993).

60. Cunningham ST, Kelley AE. Hyperactivity and sensitization topsychostimulants following cholera toxin infusion into thenucleus accumbens. J Neuroscience 13:2342-2350 (1993).

61. Antelman SM, Caggiula AR, Kocan D, Knopf S, Meyer D,Edwards DJ, Barry H. One experience with "lower" or "higher"intensity stressors respectively enhances or diminishes respon-siveness to haloperidol weeks later: implications for understand-ing drug variability. Brain Res 566:276-283 (1991).

62. vonEuler G, Ogren S, Eneroth P, Fuxe K, Gustafsson J.Persistent effects of 80 ppm toluene on dopamine-regulatedlocomotor activity and prolactin secretion in the male rat.Neurotoxicology 15:621-624 (1994).

63. Sorg BA, Willis JR, Nowatka TC, Ulibarri C, See RE,Westberg HH. A proposed animal neurosensitization model formultiple chemical sensitivity in studies with formalin.Toxicology 111:135-145 (1996).

64. Antelman SM, Caggiula AR, Kiss S, Edwards DJ, Kocan D,Stiller R. Neurochemical and physiological effects of cocaineoscillate with sequential drug treatment: possibly a major factorin drug variability. Neuropsychopharmacology 12:297-306(1995).

65. Weiss SRB, Post RM, Costello M, Nutt DJ, Tandeciarz S.Carbamazepine retards the development of cocaine-kindledseizures but not sensitization to cocaine-induced hyperactivity.Neuropsychopharmacology 3:273-281 (1990).

66. Eikelboom R, Stewart J. Conditioning of drug-induced physio-logical responses. Psychol Rev 89:507-528 (1982).

67. Badiani A, Browman KE, Robinson TE. Influence of novel ver-sus home environments on sensitization to the psychomotorstimulant effects of cocaine and amphetamine. Brain Res674:291-298 (1995).

68. Newlin DB, Thomson JB. Chronic tolerance and sensitizationto alcohol in sons of alcoholics. Alc Clin Exp Res 15:399-405(1991).

69. Stewart J, Vezina P. Extinction procedures abolish conditionedstimulus control but spare sensitized responding to ampheta-mine. Behav Pharmacol 2:65-71 (1991).

70. Post RM, Weiss SRB, Pert A. The role of context and condi-tioning in behavioral sensitization to cocaine. PsychopharmBull 23:425-429 (1987).

71. Jodogne C, Marinelli M, LeMoal M, Piazza PV. Animals pre-disposed to develop amphetamine self-administration showhigher susceptibility to develop contextual conditioning of bothamphetamine-induced hyperlocomotion and sensitization.Brain Res 657:236-244 (1994).

72. Antelman SM, Eichler AJ, Black CA, Kocan D.Interchangeability of stress and amphetamine in sensitization.Science 207:329-331 (1980).

73. Kalivas PW, Richardson-Carlson R, van Orden G. Cross-sensi-tization between foot shock stress and enkephalin-inducedmotor activity. Biol Psychiatry 21:939-950 (1986).

74. Deroche V, Piazza PV, Casolini P, LeMoal M, Simon H.Sensitization to the psychomotor effects of amphetamine andmorphine induced by food restriction depends on corticos-terone secretion. Brain Res 611:352-356 (1993).

75. Badiani A, Morano MI, Akil H, Robinson TE. Circulatingadrenal hormones are not necessary for the development of sen-sitization to the psychomotor activating effects of ampheta-mine. Brain Res 673:13-24 (1995).

76. Peris J, Decambre N, Coleman-Hardee ML, Simkins JW.Estradiol enhances behavioral sensitization to cocaine andamphetamine-stimulated striatal [3H]dopamine release. BrainRes 566:255-264 (1991).

77. Robinson TE, Becker JB, Presty SK. Long-term facilitation ofamphetamine-induced rotational behavior and striataldopamine release produced by a single exposure to ampheta-mine: sex differences. Brain Res 253:231-241 (1982).

78. Robinson TE, Berridge KC. The neural basis of drug craving:an incentive-sensitization theory of addiction. Brain Res Rev18:247-291 (1993).

79. Yehuda R, Antelman SM. Criteria for rationally evaluating ani-mal models of posttraumatic stress disorder. Biol Psychiatry33:479-486 (1993).

80. Post RM. Transduction of psychosocial stress into the neurobi-ology of recurrent affective disorder. Am J Psychiatry149:999-1010 (1992).

81. Bell IR. Clinically relevant EEG studies and psychophysiologi-cal findings: possible neural mechanisms for multiple chemicalsensitivity. Toxicology 111: 101-117 (1996).

82. Beatty J, Greenberg A, Deibler WP. Operant control of occipi-tal theta rhythm affects performance in a radar monitoringtask. Science 183:871-873 (1974).

83. Bell IR, Schwartz GE, Peterson JM, Kline JP. Unpublished data.84. Mann CA, Lubar JF, Zimmerman AW, Miller CA, Muenchen

RA. Quantitative analysis of EEG in boys with attention-deficit/hyperactivity disorder: controlled study with clinicalimplications. Ped Neurol 8:30-36 (1992).

85. Janzen T, Graap K, Stephanson S, Marshall W, FitzsimmonsG. Differences in baseline EEG measures for ADD and nor-mally achieving preadolescent males. Biofeedback Self-Regul20:65-82 (1995).

86. Bell IR, Miller CS, Schwartz GE, Peterson JM, Amend D.Neuropsychiatric and somatic characteristics of young adults


BELL ET AL.

with and without self-reported chemical odor intolerance andchemical sensitivity. Arch Environ Health 51:9-21 (1996).

87. Russell V, deVilliers A, Sagvolden T, Lamm M, Taljaard J.Altered dopaminergic function in the prefrontal cortex, nucleusaccumbens and caudate-putamen of an animal model of atten-tion-deficit/hyperactivity disorder-the spontaneously hyper-tensive rat. Brain Res 676:343-351 (1995).

88. Bell IR, Schwartz GE, Bootzin RR, Wyatt JK. Time-dependentsensitization of heart rate and blood pressure over multiple lab-oratory sessions in elderly individuals with chemical odor intol-erance. Arch Environ Health (in press).

89. Casale TB, Bowman S, Kaliner M. Induction of human cuta-neous mast cell degranulation by opiates and endogenous opi-oid peptides: evidence for opiate and nonopiate receptorparticipation. J Allergy Clin Immunol 73:775-781 (1984).

90. Baldwin CM, Bell IR, Lebowitz MD. The association of respi-ratory problems in a community sample of self-reported chemi-cal intolerance: implications for women's health and quality oflife. Eur J Epidemiol (in press).

91. McCubbin JA. Stress and endogenous opioids: behavioral andcirculatory interactions. Biol Psychology 35:91-122 (1993).

92. Bell IR, Bootzin RR, Ritenbaugh C, Wyatt JK, DeGiovanni G,Kulinovich T, Anthony J, Kuo TF, Rider SP, Peterson JM,Schwartz GE, Johnson KA. A polysomnographic study of sleepdisturbance in community elderly with self-reported environ-mental chemical odor intolerance. Biol Psychiatry 40:123-133(1996).

93. Nicholson AN, Pascoe PA. Dopaminergic transmission and thesleepTwakefulness continuum in man. Neuropharmacology29:41-417 (1990).

94. Coopersmith R, Weihmuller FB, Kirstein CL, Marshall JF,Leon M. Extracellular dopamine increases in the neonatalolfactory bulb during odor preference training. Brain Res564:149-153 (1991).

95. Martin JB, Reichlin S. Reulation of prolactin secretion and itsdisorders. In: Clinicat Neuroendocrinology. 2nd ed.Philadelphia:FA Davis, 1987;201-225.

96. Gregerson KA, Chuknyiska R, Golesorkhi N. Stimulation ofprolactin release by dopamine withdrawal: role of calciuminflux. Am J Physiol 267(5 Pt 1):E789-794 (1994).

97. Lozoff B, Felt BT, Nelson EC, Wolf AW, Meltzer HW,Jimenez E. Serum prolactin levels and behavior in infants. BiolPsychiatry 37:4-12 (1995).

98. Bell IR, Schwartz GE, Baldwin CM. Unpublished data.99. Cohen S, Kessler RC, Gordon LU, eds. Measuring Stress. A

Guide for Health and Social Scientists. New York:OxfordUniversity Press, 1995.

100. Bell IR, Schwartz GE, Baldwin CM, Hardin EE. Neural sensi-tization and physiological markers in multiple chemical sensi-tivity. Regul Toxicol Pharmacol 24:S39-S47 (1996).

101. Antelman SM, Caggiula AR, Knopf S, Kocan DJ, Edwards DJ.Amphetamine or haloperidol 2 weeks earlier antagonized theplasma corticosterone response to amphetamine: evidence forthe stressful/foreign nature of drugs. Psychopharmacology107:331-336 (1992).

102. Antelman SM, Kocan D, Kno f S, Edwards DJ, Caggiula AR.One brief exposure to a psychological stressor induces ong-last-ing, time-dependent sensitization of both the cataleptic andneurochemical responses to haloperidol. Life Sci 51:261-266(1992).

103. Staudenmayer H, Selner JC, Buhr MP. Double-blind provoca-tion chamber challenges in 20 patients presenting with "multi-ple chemical sensitivity." Regul Toxicol Pharmacol 18:44-53(1993).

104. Newlin DB, Pretorius MB. Prior exposures to the laboratoryenhance the effect of alcohol. J Stud Alc 52:470-473 (1991).

105. Groves PM, Thompson RF. Habituation: a dual-process the-ory. Psychol Rev 77:419-450 (1970).

106. Post RM. Intermittent versus continuous stimulation: effect ofthe interval on the development of sensitization or tolerance.Life Sci 26:1275-1282 (1980).

107. Piazza PV, Maccari S, Deminiere JM, LeMoal M, Mormede P,Simon H. Corticosterone levels determine individual vulnera-bility to amphetamine self-administration. Proc Natl Acad SciUSA 88:2088-2092 (1991).

108. Exner E, Clark D. Behavior in the novel environment predictsresponsiveness to d-amphetamine in the rat: a multivariateapproach. Behav Pharmacol 4:47-56 (1993).

109. Bell IR, Schwartz GE, Baldwin CM, Hardin EE, Kline JP.Unpublished data.

466 Environmental Health Perspectives * Vol 105, Supplement 2 * March 1997

hardin,' - emerge...

Documents