Claudia S. Miller

An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders.

This paper reviews the clinical and experimental literature on patients with multiple adverse responses to chemicals (Multiple Chemical Sensitivity Syndrome-MCS) and develops a model for MCS based on olfactory-limbic system dysfunction that overlaps in part with Posts kindling model for affective disorders. MCS encompasses a broad range of chronic polysymptomatic conditions and complaints whose triggers are reported to include low levels of common indoor and outdoor environmental chemicals, such as pesticides and solvents. Other investigators have found evidence of increased prevalence of depression, anxiety, and somatization disorders in MCS patients and have concluded that their psychiatric conditions account for the clinical picture. However, none of these studies has presented any data on the effects of chemicals on symptoms or on objective measures of nervous system function. Synthesis of the MCS literature with large bodies of research in neurotoxicology, occupational medicine, and biological psychiatry, suggests that the phenomenology of MCS patients overlaps that of affective spectrum disorders and that both involve dysfunction of the limbic pathways. Animal studies demonstrate that intermittent repeated low level environmental chemical exposures, including pesticides, cause limbic kindling. Kindling (full or partial) is one central nervous system mechanism that could amplify reactivity to low levels of inhaled and ingested chemicals and initiate persistent affective, cognitive, and somatic symptomatology in both occupational and nonoccupational settings. As in animal studies, inescapable and novel stressors could cross-sensitize with chemical exposures in some individuals to generate adverse responses on a neurochemical basis. The olfactory-limbic model raises testable neurobiological hypotheses that could increase understanding of the multifactorial etiology of MCS and of certain overlapping affective spectrum disorders.

The Environmental Exposure and Sensitivity Inventory (EESI): a standardized approach for measuring chemical intolerances for research and clinical applications:

The lack of a generally accepted case definition for multiple chemical sensitivity (MCS) and the absence of a standardized approach for measuring salient aspects of chemical sensitivity that would permit cross-comparison of findings by different investigators have hindered progress in this area. Based upon findings from an earlier study of 112 persons with self-reported chemical sensitivity who attributed their chemical sensitivity to a well-defined exposure event, we developed an instrument with self-rating scales to assess Symptom Severity, Chemical (Inhalant) Intolerances, Other Intolerances (e.g., foods, medications, alcohol), Life Impact, and Masking (a measure of ongoing chemical exposures). When administered to four patient groups and controls, the scales showed good reliability and validity overall (n=421) and in each group. Used together, the scales provided sensitivity of 92% and specificity of 95% in differentiating chemically sensitive persons from controls. Our results support use of these scales individually or collectively for a variety of applications including the selection of chemically sensitive subjects and controls for research, assessment of chemical sensitivity in various study populations, cross-comparison of groups studied by different investigators, pre- and post-assessment of therapeutic interventions, clinical evaluation of complex patients who report intolerances, and teaching medical residents and students how to evaluate patients for chemical sensitivity and MCS.

Chemical Sensitivity Attributed to Pesticide Exposure versus Remodeling

One hundred twelve individuals who reported onset of multiple chemical sensitivity following well-documented exposure to either (1) a cholinesterase-inhibiting organophosphate or carbamate pesticide or (2) remodeling of a building completed mail-out/mail-back questionnaires concerning their exposure, symptoms, sensitivity to ingestants and inhalants, utilization of health-care resources, and impact of their illness on lifestyle. It was hypothesized that if multiple chemical sensitivity resulted from neurotoxic exposure, then organophosphate-exposed respondents should report greater severity of illness resulting from the relatively greater neurotoxicity of this class of chemicals. Pesticide-exposed and remodeling-exposed multiple chemical sensitivity groups reported similar patterns of symptoms and identified similar inhalants and ingestants as triggers for their symptoms; these results suggested a common mechanism (biological and/or psychological) for their conditions. The pesticide-exposed group, however, reported significantly greater symptom severity than did the remodeling-exposed group, especially for neuromuscular, affective, airway, gastrointestinal, and cardiac symptoms. These findings provide evidence for (1) a possible biological basis for multiple chemical sensitivity and (2) a distinct pathophysiology or final common pathway for the condition that, while as yet undefined, appears to be shared by these two groups. Although subjective multisystem health complaints characterize both multiple chemical sensitivity and somatoform disorder, features of this multiple chemical sensitivity sample were inconsistent with somatoform disorder, i.e., onset after 30 y of age in 83%, the predominance of severe cognitive symptoms, and attributions of environmental causation. No group differences were found with respect to lifestyle impact. Eighty-one percent of respondents said they had been working full-time at the time they were exposed, yet at the time of the survey (on average, 7.7 y post exposure) only 12.5% were working full-time. The majority said they had quit their jobs, changed jobs, or changed careers because of their illness. Approximately 40% reported that they had consulted 10 or more medical practitioners. The persistent, disabling neuropsychological symptoms reported by these multiple chemical sensitivity groups are strikingly similar to those reported among individuals exposed occupationally to pesticides and solvents. These parallel findings suggest that the types and levels of exposures associated with extermination and remodeling may not be inconsequential, at least for a subset of the population. Further studies from a variety of perspectives, including human challenge studies and the development of animal models, are needed to define the pathophysiological and psychological mechanisms underlying this costly condition.

Potential animal model of multiple chemical sensitivity with cholinergic supersensitivity

Multiple Chemical Sensitivity (MCS) is a clinical phenomenon in which individuals, after acute or intermittent exposure to one or more chemicals, commonly organophosphate pesticides (OPs), become overly sensitive to a wide variety of chemically-unrelated compounds, which can include ethanol, caffeine and other psychotropic drugs. The Flinders Sensitive Line (FSL) rats were selectively bred to be more sensitive to the OP diisopropylfluorophosphate (DFP) compared to their control counterparts, the Flinders Resistant Line (FRL) rats. The present paper will summarize evidence which indicates that the FSL rats exhibit certain similarities to individuals with MCS. In addition to their greater sensitivity to DFP, the FSL rats are more sensitive to nicotine and the muscarinic agonists arecoline and oxotremorine, suggesting that the number of cholinergic receptors may be increased, a conclusion now supported by biochemical evidence. The FSL rats have also been found to exhibit enhanced responses to a variety of other drugs, including the serotonin agonists m-chlorophenylpiperazine and 8-OH-DPAT, the dopamine antagonist raclopride, the benzodiazepine diazepam, and ethanol. MCS patients report enhanced responses to many of these drugs, indicating some parallels between FSL rats and MCS patients. The FSL rats also exhibit reduced activity and appetite and increased REM sleep relative to their FRL controls. Because these behavioral features and the enhanced cholinergic responses are also observed in human depressives, the FSL rats have been proposed as a genetic animal model of depression. It has also been reported that MCS patients have a greater incidence of depression, both before and after onset of their chemical sensitivities, so cholinergic supersensitivity may be a state predisposing individuals to depressive disorders and/or MCS. Further exploration of the commonalities and differences between MCS patients, human depressives, and FSL rats will help to elucidate the mechanisms underlying MCS and could lead to diagnostic approaches and treatments beneficial to MCS patients.

The Compelling Anomaly of Chemical Intolerance

Abstract: In science, anomalies expose the limitations of existing paradigms and drive the search for new ones. In the late 1800s, physicians observed that certain illnesses spread from sick, feverish individuals to those contacting them, paving the way for the germ theory of disease. The germ theory served as a crude, but elegant formulation that explained dozens of seemingly unrelated illnesses affecting literally every organ system. Today, we are witnessing another medical anomaly—a unique pattern of illness involving chemically exposed groups in more than a dozen countries, who subsequently report multisystem symptoms and new‐onset chemical, food, and drug intolerances. These intolerances may be the hallmark for a new disease process or paradigm, just as fever is a hallmark for infection. The fact that diverse demographic groups, sharing little in common except some initial chemical exposure event, develop these intolerances is a compelling anomaly pointing to a possible new theory of disease, one that has been referred to as “Toxicant‐Induced Loss of Tolerance” (“TILT”). TILT has the potential to explain certain cases of asthma, migraine headaches, and depression, as well as chronic fatigue, fibromyalgia, and “Gulf War syndrome”. It appears to evolve in two stages: (1) initiation, characterized by a profound breakdown in prior, natural tolerance resulting from either acute or chronic exposure to chemicals (pesticides, solvents, indoor air contaminants, etc.), followed by (2) triggering of symptoms by small quantities of previously tolerated chemicals (traffic exhaust, fragrances, gasoline), foods, drugs, and food/drug combinations (alcohol, caffeine). While the underlying dynamic remains an enigma, observations indicating that affected individuals respond to structurally unrelated drugs and experience cravings and withdrawal‐like symptoms, paralleling drug addiction, suggest that multiple neurotransmitter pathways may be involved.

Chemical intolerance in primary care settings: prevalence, comorbidity, and outcomes.

PURPOSE This study extends previous community-based studies on the prevalence and clinical characteristics of chemical intolerance in a sample of primary care clinic patients. We evaluated comorbid medical and psychiatric disorders, functional status, and rates of health care use. METHODS A total of 400 patients were recruited from 2 family medicine clinic waiting rooms in San Antonio, Texas. Patients completed the validated Quick Environmental Exposure and Sensitivity Inventory (QEESI) to assess chemical intolerance; the Primary Care Evaluation of Mental Disorders (PRIME-MD) screen for possible psychiatric disorders; the Dartmouth–Northern New England Primary Care Cooperative Information Project (Dartmouth COOP) charts for functional status; and the Healthcare Utilization Questionnaire. RESULTS Overall, 20.3% of the sample met criteria for chemical intolerance. The chemically intolerant group reported significantly higher rates of comorbid allergies and more often met screening criteria for possible major depressive disorder, panic disorder, generalized anxiety disorder, and alcohol abuse disorder, as well as somatization disorder. The total number of possible mental disorders was correlated with chemical intolerance scores (P <.001). Controlling for demographics, patients with chemical intolerance were significantly more likely to have poorer functional status, with trends toward increased medical service use when compared with non–chemically intolerant patients. After controlling for comorbid psychiatric conditions, the groups differed significantly only regarding limitations of social activities. CONCLUSIONS Chemical intolerance occurs in 1 of 5 primary care patients yet is rarely diagnosed by busy practitioners. Psychiatric comorbidities contribute to functional limitations and increased health care use. Chemical intolerance offers an etiologic explanation. Symptoms may resolve or improve with the avoidance of salient chemical, dietary (including caffeine and alcohol), and drug triggers. Given greater medication intolerances in chemical intolerance, primary care clinicians could use the QEESI to identify patients for appropriate triage to comprehensive nonpharmacologic care.

The new tapestry of risk assessment

Neurotoxicology is entering a new phase in how it views and practices risk assessment. Perhaps more than any of the other disciplines that comprise the science of toxicology, it has been compelled to consider a daunting array of factors other than those directly coupled to chemical and dose, and the age and sex of the subject population. In epidemiological investigations, researchers are increasingly cognizant of the problems introduced by allegedly controlling for variables classified as confounders or covariates. In essence, they reason, the consequence is blurring or even concealing interactions of exposure with modifiers such as the individuals social ecology. Other researchers question the traditional practice of relying on values such as NOAELs when they are abstracted from a biological entity that in reality represents a multiplicity of intertwined systems. Although neurotoxicologists have come to recognize the complexities of assessing risk in all its dimensions, they still face the challenge of communicating this view to the health professions at large.

Maternal Chemical and Drug Intolerances: Potential Risk Factors for Autism and Attention Deficit Hyperactivity Disorder (ADHD)

Purpose: The aim of this study was to assess whether chemically intolerant women are at greater risk for having a child with autism spectrum disorders (ASD) or attention deficit hyperactivity disorder (ADHD). Methods: We conducted a case–control study of chemical intolerance among mothers of children with ASD (n = 282) or ADHD (n = 258) and children without these disorders (n = 154). Mothers participated in an online survey consisting of a validated chemical intolerance screening instrument, the Quick Environmental Exposure and Sensitivity Inventory (QEESI). Cases and controls were characterized by parental report of a professional diagnosis. We used a one-way, unbalanced analysis of variance to compare means across the 3 groups. Results: Both mothers of children with ASD or ADHD had significantly higher mean chemical intolerance scores than did mothers of controls, and they were more likely to report adverse reactions to drugs. Chemically intolerant mothers were 3 times more likely (odds ratio, 3.01; 95% confidence interval, 1.50–6.02) to report having a child with autism or 2.3 times more likely (odds ratio, 2.3; 95% confidence interval, 1.12–5.04) to report a child with ADHD. Relative to controls, these mothers report their children are more prone to allergies (P < .02), have strong food preferences or cravings (P < .003), and have greater sensitivity to noxious odors (P < .04). Conclusion: These findings suggest a potential association between maternal chemical intolerance and a diagnosis of ADHD or ASD in their offspring.

Cognitive performance and cerebrohemodynamics associated with the Persian Gulf Syndrome

The Persian Gulf Syndrome generally manifests as a set of nonspecific complaints with emphasis on central nervous system impairment. The purpose of this study was to determine if cognitive performance and middle cerebral artery blood flow velocity (MCABFV) were altered in symptomatic Gulf War veterans (sGWVs) and asymptomatic Gulf War veterans (aGWVs) by exposure to low levels of acetone. MCABFV was assessed in male aGWVs (n=8) and sGWVs (n=8) during cognitive challenges while breathing 1) clean air, 2) a clean air placebo, and 3) a mixture of air and 40 parts per million (ppm) acetone. Pulmonary function was also evaluated. Pulmonary function tests showed no statistical differences between aGWVs and sGWVs while breathing clean air or 40 ppm acetone in air. Cognitive performance was similar during the clean air, placebo, and acetone test conditions for sGWVs and aGWVs. Data pooled across test conditions for each group indicated a statistically significant (P <0.05) poorer performance primarily in memory and executive function tasks by sGWVs. sGWVs had a 34.2% higher baseline MCABFV than aGWVs (P <0.05). Increases in MCABFV for aGWVs (averaged over all cognitive tasks for each test condition) ranged between 7.8% and 8.8%, and were not statistically significant. Increases for sGWVs ranged between 0.3% and 4.8%, averaged over all cognitive tasks for each test condition. No significant differences were noted between the clean air and placebo test conditions but both were significantly different compared to the acetone condition. Differences in MCABFV increases for each of the test conditions between aGWVs and sGWVs were also statistically significant. sGWV did not appear to demonstrate pulmonary dysfunction following exposure to acetone. They did, however, appear to have generally lower cognitive function as compared to aGWVs. sGWVs appeared to have a significant degree of autoregulatory disruption in cerebral perfusion, resulting in reduced cognitive reserve capacity and potentially impaired ability to handle complex cognitive tasks.

Acetaminophen, pesticide, and diethylhexyl phthalate metabolites, anandamide, and fatty acids in deciduous molars: potential biomarkers of perinatal exposure.

The developing fetus is particularly vulnerable to adverse effects from pharmaceutical and exogenous chemical exposure. Deciduous teeth primarily form over specific periods from the second trimester in utero through the months after birth. We hypothesized that organic chemicals or their metabolites circulating in the bloodstream may sorb into forming dental tissues and remain stored in the tooth thereafter. Our aims were to devise analytical and preparation methods for potentially toxic or beneficial organic chemicals or metabolites in deciduous teeth and to estimate their detection frequencies. The analgesic acetaminophen was stored at greater concentration in a childs second molar than a first molar, consistent with intake, suggesting that acetaminophen concentration in molars may be a biomarker of acetaminophen exposure during molar formation. Chemicals detected by liquid chromatography/tandem mass spectrometry in molars of 21 typically developing children include the endocannabinoid anandamide (86% of children), acetaminophen (43%), and specific metabolites mono-2-ethylhexyl phthalate (MEHP, of plasticizer di-2-ethylhexyl phthalate, 29%), 3,5,6-trichloro-2-pyridinol (TCPy, of organophosphate (OP) insecticide chlorpyrifos, 10%), and 2-isopropyl-6-methyl-4-pyrimidinol (IMPy, of OP insecticide diazinon, 10%). None of these chemicals has previously been detected in human teeth. Molars from the two oldest subjects contained the largest concentrations of MEHP, TCPy, and IMPy. Potentially protective fatty acids detected by gas chromatography/mass spectrometry after derivatization include docosahexaenoic (19%), arachidonic (100%), and linoleic (100%). Validation studies are necessary to verify that each detected chemical in molars provides a biomarker of perinatal exposure.