Low Levels Of Environmental Chemicals Research Articles

'Environmental standard limit concentration' arsenic exposure is associated with anxiety, depression, and autism-like changes in early-life stage zebrafish

Arsenic is a worldwide environmental pollutant that can impair human health. Previous studies have identified mental disorders induced by arsenic, but the environmental exposure concentrations in the early life stages associated with these disorders are poorly understood. In the present study, early-life stage zebrafish were used to explore the effects on mental disorders under 'environmental standard limit concentrations' arsenic exposures of 5, 10, 50, 150, and 500 μg/L. The results showed that arsenic exposure at these concentrations changed the locomotor behavior in larval zebrafish and was further associated with anxiety, depression, and autism-like behavior in both larval and juvenile zebrafish. Changes were noted at benchmark dose limit (BMDL) concentrations as low as 0.81 μg/L. Transcriptomics showed that immediate early genes (IEGs) fosab, egr1, egr2a, ier2b, egr3, and jund were decreased after arsenic exposure in larval and juvenile zebrafish. Nervous system impairment and anxiety, depression, and autism-like behaviors in early-life stage zebrafish at 'environmental standard limit concentrations' may be attributed to the downregulation of IEGs. These findings in zebrafish provided new experimental support for an arsenic toxicity threshold for mental disorders, and they suggest that low levels of environmental chemicals may be causative developmental factors for mental disorders.

Levels of non-essential trace metals and their impact on placental health: a review.

According to recent research, even low levels of environmental chemicals, particularly heavy metals, can considerably disrupt placental homeostasis. This review aims to explore the profile of non-essential trace metals in placental tissues across the globe and to specify trace metal(s) that can be candidates for impaired placental health. Accordingly, we conducted an extensive survey on relevant databases of peer-reviewed papers published in the last two decades. Among a considerable number of non-essential trace metals, arsenic (As), lead (Pb), cadmium (Cd), and mercury (Hg) were identified as the most detrimental to placental health. Comparative analysis showed remarkable differences in placental levels of these trace metals worldwide. Based on current data reported across the globe, a median (min-max) range from 0.55 to 15ng/g for placental As levels could be deemed safe. The placental Cd and Pb levels were markedly higher in smokers than in non-smokers. Occupationally exposed pregnant women had several orders of magnitude higher Cd, Pb, and Hg levels in placental tissues than non-occupationally exposed women. Also, we concluded that even low-level exposure to As, Cd, Pb, and Hg could be deleterious to proper fetal development. This review implies the need to reduce exposure to non-essential trace metals to preserve placental health and prevent numerous poor pregnancy outcomes. Overall, the information presented is expected to help plan future fundamental and applied investigations on the placental toxicity of As, Cd, Pb, and Hg.

The use of biomonitoring data in exposure and human health risk assessments.

Biomonitoring uses analytic methods that permit the accurate measurement of low levels of environmental chemicals in human tissues. However, depending on the intended use, biomonitoring, like all exposure tools, may not be a stand-alone exposure assessment tool for some of its environmental public health uses. Although biomonitoring data demonstrate that many environmental chemicals are absorbed in human tissues, uncertainty exists regarding if and at what concentrations many of these chemicals cause adverse health outcomes. Moreover, without exposure pathway information, it is difficult to relate biomonitoring results to sources and routes of exposure and develop effective health risk management strategies. In September 2004, the Health and Environmental Sciences Institute, U.S. Environmental Protection Agency, Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry, and International Council of Chemical Associations co-sponsored the International Biomonitoring Workshop, which explored the processes and information needed for placing biomonitoring data into perspective for risk assessment purposes, with special emphasis on integrating biomarker measurements of exposure, internal dose, and potential health outcome. Scientists from international governments, academia, and industry recommended criteria for applying biomonitoring data for various uses. Six case studies, which are part of this mini-monograph, were examined: inorganic arsenic, methyl eugenol, organophosphorus pesticides, perfluorooctanesulfonate, phthalates, and polybrominated diphenyl ethers. Based on the workshop and follow-up discussions, this overview article summarizes lessons learned, identifies data gaps, outlines research needs, and offers guidance for designing and conducting biomonitoring studies, as well as interpreting biomonitoring data in the context of risk assessment and risk management.

Elevated Basal Expression of Liver Peroxisomal β-Oxidation Enzymes and CYP4A Microsomal Fatty Acid ω-Hydroxylase in STAT5b−/− Mice: Cross-Talk in Vivo between Peroxisome Proliferator-Activated Receptor and Signal Transducer and Activator of Transcription Signaling Pathways

Long-term treatment of rodents with peroxisome proliferator chemicals, a group of structurally diverse nongenotoxic carcinogens, leads to liver cancer in a process dependent on the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα). Previous in vitro studies have shown that growth hormone (GH) can inhibit PPARα-dependent gene expression by down-regulation of PPARα expression and by a novel inhibitory cross-talk involving the GH-activated transcription factor STAT5b. Presently, we evaluate the role of STAT5b in mediating these inhibitory actions of GH on PPAR function using a STATb-deficient mouse model. Protein levels of three PPARα-responsive peroxisomal β-oxidation pathway enzymes (fatty acyl-CoA oxidase, 3-ketoacyl-CoA thiolase, and l-bifunctional enzyme) were increased up to two- to threefold in STAT5b−/− relative to wild-type control mouse liver, as was the basal expression of two PPARα-regulated cytochrome P450 4A proteins. In contrast, protein levels of two PPARα-unresponsive peroxisomal enzymes, catalase and urate oxidase, were not affected by the loss of STAT5b. A corresponding increase in expression of fatty acyl-CoA oxidase and l-bifunctional enzyme mRNA, as well as PPARα mRNA, was observed in the STAT5b-deficient mice, suggesting a transcriptional mechanism for the observed increases. Although basal liver expression of PPARα and its target genes was thus elevated in STAT5b−/− mice, the clofibrate-induced level of enzyme expression was unaffected, suggesting that the inhibitory effects of STAT5b are overcome at high concentrations of PPARα activators. These findings support the hypothesis that GH and potentially other endogenous activators of STAT5b help to maintain liver PPARα function at a low basal level and may thereby moderate PPARα-dependent hepatocarcinogenesis and other responses stimulated by exposure to low levels of environmental chemicals of the peroxisome proliferator class.

EEG Beta 1 Oscillation and Sucrose Sensitization in Fibromyalgia with Chemical Intolerance

Patients with fibromyalgia (FM) have diffuse musculoskeletal pain; half report concomitant intolerance for low levels of environmental chemicals (CI). Previous investigators have hypothesized that the chronic pain and chemical intolerance reflect sensitization of different central nervous system limbic and/or mesolimbic reward pathways. We evaluated electroencephalographic (EEG) beta activity and blood glucose responses of FM patients with and without CI and normals during three repeated sucrose ingestion sessions and during a final, water-only session (testing for conditioning). The FM with CI exhibited oscillation (reversal in direction of change from session to session) at rest and then sensitization (progressive amplification) of EEG beta I over time across the 3 sucrose sessions versus controls. FM with CI showed sensitization of blood glucose over the 3 sucrose sessions, which, like the EEG findings, reverted toward baseline in the final water-only session. The data suggest that the subset of FM patients with CI have increased susceptibility to oscillation and physiological sensitization without conditioning, perhaps contributing to fluctuations in their chronic course.

Concomitant Environmental Chemical Intolerance Modifies the Neurobehavioral Presentation of Women with Fibromyalgia

ABSTRACTBackground: This study compared personality, dietary, and psychophysiological characteristics of 3 groups of women: fibro-myalgia (FM) with illness from low levels of environmental chemicals (chemical intolerance, CI), FM alone without CI, and normal controls. CI may be a marker for enhanced central nervous system response amplification (sensitization) in limbic and mesolimbic pathways, which play a role in hedonic responses to food and drugs and in pain.Method: Fibromyalgic women with (FM/CI, n = 11) and without CI (FM, n = 10) and normals (NORM, n = 10) participated in the study. Measures included psychological trait questionnaires, a food frequency questionnaire, a taste test for hedonic and sweetness ratings of different sucrose concentrations, pain self-ratings, and resting spectral electro-encephalographic alpha over midline sites, averaged over four separate days.Results: FM with CI had the highest scores on the Harm Avoidance dimension of the Tridimensional Personality Questionnaire, Carbo...

Idiopathic Environmental Intolerances (IEI) - früher Multiple Chemical Sensitivity (MCS) - aus psychiatrischer Sicht

The term "idiopathic environmental intolerances" (IEI)/"multiple chemical sensitivities" (MCS) is used to describe a complex of heterogeneous somatic symptoms without a diagnosable organic disease. Symptoms are believed to be triggered by exposure to low levels of environmental chemicals that are usually well tolerated by the general population. There is no widely accepted definition for the phenomenon. A number of contradictory etiologic hypotheses and therapeutic concepts are discussed. One of the crucial questions is whether IEI/MCS should be understood as an own entity of disease. It has been demonstrated that a majority of patients with IEI/MCS meet diagnostic criteria for psychiatric diseases. Most frequently, somatoform, affective and anxiety disorders can be diagnosed. Therefore, psychiatric and psychotherapeutic therapy seems appropriate. The present paper provides a review of the different case definitions, etiologic and therapeutic concepts and of studies examining the frequency of psychiatric morbidity in patients with IEI/MCS. Additionally, a diagnostic algorithm and a concept of behavioral therapy for IEI/MCS patients with somatoform disorders are described.

Patterns of Waking Eeg Spectral Power in Chemically Intolerant Individuals During Repeated Chemical Exposures

Previous studies indicate that low level chemical intolerance (CI) is a symptom of several different controversial conditions with neuropsychiatric features, e.g., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and “Persian Gulf Syndrome”. Prior studies suggest that limbic and/or mesolimbic sensitization may contribute to development of CI. The purpose of this report was to document the waking electroencephalographic (EEG) patterns of individuals with CI during chemical exposures presented over repeated sessions. Three groups of adult subjects who were recruited from the community participated in the study: self-reported CI who had made associated lifestyle changes due to their intolerance (CI/ LSC), self-reported CI who had not made such changes (CI), and normal controls without self-reported CI. Subjects underwent two sessions involving one-minute EEG recordings during exposures to low level chemical odors (a probe for limbic activation). The CI, but not the CI/ LSC, subjects had increased absolute delta power after the chemical exposures during the second, but not the first, session. The findings support the neural sensitization hypothesis for intolerance to low levels of environmental chemicals in vulnerable individuals. As in human

Differing Patterns of Cognitive Dysfunction and Heart Rate Reactivity in Chemically-Intolerant Individuals With and Without Lifestyle Changes

AbstractThe purpose of the present study was to compare specific neuropsychological, psychological, and family history patterns, as well as cardiovascular reactivity of three community-recruited groups of nonsmoking, nonalcoholic middle-aged individuals with and without the symptom of intolerance to low levels of environmental chemicals (CI). CI is a common symptom in chronic fatigue syndrome and fibro-myalgia. The groups included: (i) CI who had made associated lifestyle changes because of the CI (CI/LSC); (ii) CI who had not made such changes (CI); and (iii) normals without CI (N). All subjects underwent an evaluation session followed by two laboratory cognitive and psycho-physiological test sessions one week apart. The CI/LSC diverged from the other groups in exhibiting poorer performance on the Continuous Visual Memory Test (CVMT) in terms of more false alarms and fewer correct hits, but normal performance on a visuospatial test of divided attention (DAT). In contrast, the CI group showed progressivel...

Illness from low levels of environmental chemicals: relevance to chronic fatigue syndrome and fibromyalgia

This article summarizes (1) epidemiologic and clinical data on the symptoms of maladies in association with low-level chemicals in the environment, i.e., environmental chemical intolerance (CI), as it may relate to chronic fatigue syndrome (CFS) and fibromyalgia; and (2) the olfactory–limbic neural sensitization model for CI, a neurobehavioral synthesis of basic and clinical research. Severe CI is a characteristic of 20–47% of individuals with apparent CFS and/or fibromyalgia, all patients with multiple chemical sensitivity (MCS), and approximately 4–6% of the general population. In the general population, 15–30% report at least minor problems with CI. The levels of chemicals reported to trigger CI would normally be considered nontoxic or subtoxic. However, host factors—e.g., individual differences in susceptibility to neurohormonal sensitization (amplification) of endogenous responses—may contribute to generating a disabling intensity to the resultant multisystem dysfunctions in CI. One site for this amplification may be the limbic system of the brain, which receives input from the olfactory pathways and sends efferents to the hypothalamus and the mesolimbic dopaminergic [reward] pathway. Chemical, biologic, and psychological stimuli can initiate and elicit sensitization. In turn, subsequent activation of the sensitized limbic and mesolimbic pathways can then facilitate dysregulation of behavioral, autonomic, endocrine, and immune system functions. Research to date has demonstrated the initiation of neurobehavioral sensitization by volatile organic compounds and pesticides in animals, as well as sensitizability of cardiovascular parameters, β-endorphin levels, resting EEG α-wave activity, and divided-attention task performance in persons with CI. The ability of multiple types of widely divergent stimuli to initiate and elicit sensitization offers a new perspective on the search for mechanisms of illness in CFS and fibromyalgia with CI.

Serum Neopterin and Somatization in Women with Chemical Intolerance, Depressives, and Normals

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several controversial polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with l-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. This study compared middle-aged women with CI (who had high levels of affective distress; n = 14), depressives without CI (n = 10), and normals (n = 11). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the CI alone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of ‘unexplained’ multiple somatic symptoms in subtypes of apparent somatizing disorders.

Differential Resting Quantitative Electroencephalographic Alpha Patterns in Women with Environmental Chemical Intolerance, Depressives, and Normals

Background: Previous research suggests that a subset of individuals with intolerance to low levels of environmental chemicals have increased levels of premorbid and/or comorbid psychiatric disorders such as depression, anxiety, and somatization. The purpose of this study was to evaluate the psychological profiles and quantitative electroencephalographic (qEEG) profiles at baseline of women with and without chemical intolerance (CI). Methods: Participants were middle-aged women who reported illness from the odor of common chemicals (CI, n = 14), depressives without such intolerances (D, n = 10), and normal controls (N, n = 11). They completed a set of psychological scales and underwent two separate qEEG recording laboratory sessions spaced 1 week apart, at the same time of day for each subject. Results: CI were similar to D with increased lifetime histories of physician-diagnosed depression (71% vs. 100%), Symptom Checklist 90 (revised) (SCL-90-R) so-matization scores, Barsky Somatic Symptom Amplification, and perceived life stressfulness, although D had more distress than either CI or N on several other SCL-90-R subscales. CI scored significantly higher on the McLean Limbic Symptom Checklist somatic symptom subscale than did either D or N. On qEEG, CI exhibited significantly greater overall resting absolute alpha activity with eyes closed, especially at the parietal midline site (Pz), and increased (sensitized) frontal alpha from session 1 to 2, in contrast with the D and N groups. D showed right frontal asymmetry in both sessions, in comparison with CI. Conclusions: The data indicate that CI with affective distress diverge from both D without chemical intolerance and N in qEEG alpha patterns at resting baseline. Although CI descriptively resemble D with increased psychological distress, the CI’s greater alpha suggests the possibility of a) central nervous system hypo-, not hyper-, activation; and/or b) an overlap with EEG alpha patterns of persons with positive family histories of alcoholism.

VALIDATION OF A BRIEF SCREENING MEASURE OF ENVIRONMENTAL CHEMICAL SENSITIVITY: THE CHEMICAL ODOR INTOLERANCE INDEX

The development and validation of a brief self-report screening measure of environmental chemical sensitivity, the Chemical Odor Intolerance Index (CII), is described. Subjects included 1734 college students, 192 older adults, and 38 chemically intolerant and multiple chemical sensitivity (MCS) patients. The results of the studies demonstrate that the CII has strong internal stability (Cronbach's alpha ranging from 0.80 to 0.92 across samples), and evidence of factorial, group, convergent, and discriminant validity is reported across diverse samples. In future research, the CII will permit the quantification of self-reported illness from low levels of environmental chemicals as a continuous rather than dichotomous variable. Consequently, the CII will facilitate the ability to compare and standardize subject selection criteria in both preclinical and clinical (i.e. MCS) populations.

Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental chemicals.

Sensitization in the neuroscience and pharmacology literatures is defined as progressive increase in the size of a response over repeated presentations of a stimulus. Types of sensitization include stimulant drug-induced time-dependent sensitization (TDS), an animal model related to substance abuse, and limbic kindling, an animal model for temporal lobe epilepsy. Neural sensitization (primarily nonconvulsive or subconvulsive) to the adverse properties of substances has been hypothesized to underlie the initiation and subsequent elicitation of heightened sensitivity to low levels of environmental chemicals. A corollary of the sensitization model is that individuals with illness from low-level chemicals are among the more sensitizable members of the population. The Working Group on Sensitization and Kindling identified two primary goals for a research approach to this problem: to perform controlled experiments to determine whether or not sensitization to low-level chemical exposures occurs in multiple chemical sensitivity (MCS) patients; and to use animal preparations for kindling and TDS as nonhomologous models for the initiation and elicitation of MCS.

Testing the Neural Sensitization and Kindling Hypothesis for Illness from Low Levels of Environmental Chemicals

Testing the Neural Sensitization and Kindling Hypothesis for Illness from Low Levels of Environmental Chemicals

Individual differences in neural sensitization and the role of context in illness from low-level environmental chemical exposures.

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena.

Neural Sensitization and Physiological Markers in Multiple Chemical Sensitivity

This paper summarizes the key features of the olfactory-limbic, neural sensitization model for multiple chemical sensitivity (MCS) and presents relevant data on chemically intolerant human subjects from laboratory studies using quantitative electroencephalography, polysomnography, neuropsychological tests, cardiovascular measurements, and blood markers. MCS is a poorly understood chronic, polysymptomatic condition in which some prior controlled research studies have failed to find evidence to differentiate active from placebo tests. Closer examination of past MCS research, however, reveals that studies have failed to incorporate the design and methodological approaches necessary to test for nonimmunological sensitization. Time-dependent sensitization (TDS) is a well-documented phenomenon in the pharmacology literature involving the progressive increase in a given response by the passage of time between the initial and subsequent exposures to a substance or a stressor. As in MCS, multiple, chemically unrelated agents can trigger TDS. Females time-sensitize more readily than do males. Pharmacological and nonpharmacological (stress) stimuli can cross-sensitize. Dopaminergic pathways in the brain and the hypothalamic–pituitary–adrenal axis are likely involved in TDS. Data on the symptomatology of MCS point to central nervous system involvement, including limbic regions that receive input from both olfactory (odor) and trigeminal (irritant) pathways. Limbic and mesolimbic brain regions are among the most sensitizable to repeated, intermittent environmental stimuli. Sensitizable individuals can show no difference or lesser responses to a test substance on initial exposure, but later exhibit much greater increases in responsivity on the next exposure after a period of days. For future research, it is essential to distinguish chemical intolerance symptoms such as derealization, sudden mood changes, musculoskeletal pain, menstrual dysfunction, and uncontrollable sleepiness from chemical phobia and avoidance behaviors. This model permits hypothesis-driven research on MCS and has major implications for interpretation of apparently positive and negative tests for “true” as opposed to “perceived” sensitivity to low levels of environmental chemicals.

What Can Research Contribute to Regulatory Decisions about the Health Risks of Multiple Chemical Sensitivity?

Multiple Chemical Sensitivity (MCS), which may not be caused by chemicals at all, is a serious medical problem of unknown origin and uncertain etiology that raises many fundamental science and policy questions. Regulators, for example, are confronted with a dilemma: what, if anything, should be done to protect people from the scientifically uncertain health risks of exposures to extremely low levels of environmental chemicals. Regulatory agencies, such as the Environmental Protection Agency, do not have the luxury of waiting until conclusive scientific evidence is available before making a decision; however, our present lack of scientific understanding about MCS is so acute that it is not possible to ascertain whether the cause of MCS-related symptoms is chemical, biological, physical, pyschosocial, or some combination thereof. Nevertheless, many MCS sufferers and advocates for the chemically induced hypothesis are clamoring for regulatory action to reduce putative health risks from very-low-level exposures to chemicals in the environment. Unless steps are taken to improve the quantity and quality of the existing scientific data base, we cannot, with any acceptable degree of certainty, evaluate the extent to which regulatory decisions about MCS are either protective of public health or cost-effective. This article examines how research can strengthen the scientific basis for risk-related decisions about MCS, and proposes a framework for establishing research directions and priorities. It is argued that high-priority research on MCS is distinquishable by four attributes: (1) results are valuable for risk-related decisions; (2) findings significantly advance scientific knowledge and understanding; and the hypothesis being tested is both (3) biologically plausible and (4) readily testable.

Clinically relevant EEG studies and psychophysiological findings: possible neural mechanisms for multiple chemical sensitivity

This paper addresses the evidence for the face, construct, and criterion-related validity of the olfactory-limbic/ neural sensitization model for multiple chemical sensitivity (MCS). MCS is a poorly-understood, controversial condition in which low levels of environmental chemicals are reported to trigger disabling levels of illness in certain individuals. Neural sensitization processes could generate an endogenous amplification of responsivity to exogenous substances, thereby providing a plausible explanation for the apparent lack of a classical toxicological dose-response relationship in MCS. Convergent data from both survey and psychophysiological studies of MCS patients and of persons from the community without MCS, but who report elevated frequency of illness from chemical odors (cacosmics), support the involvement of the limbic system and the sensitizability of cacosmics, as predicted by the model. Recent studies show that cacosmics do sensitize their heart rate, blood pressure, and plasma β-endorphin responses to repeated exposures to a novel laboratory procedure involving dietary manipulations over time. Cacosmia may represent a pathological form of neural plasticity. Taken together, the model and the available evidence suggest the need for more intensive investigation of MCS from the standpoint of possible neurobiological mechanisms affecting cognitive, emotional, and somatic functions.

Time-dependent sensitization of plasma beta-endorphin in community elderly with self-reported environmental chemical odor intolerance

This study examined plasma beta-endorphin as a marker of the physiological stress response in community elderly who were either high (n = 15) or low (n = 15) in self-rated frequency of illness from environmental chemical odors. Individuals who report nonatopic multiple sensitivities to or intolerances for low levels of environmental chemicals also claim high rates of comorbid food sensitivities or intolerances. Subjects gave 9 AM blood samples for plasma beta-endorphin 90 min after ingesting either 1% fat cow's milk or a soy-based nondairy drink, on six different mornings in the laboratory after all-night sleep recordings. The six sessions-were divided into three sets of two successive days each, with each set [involving baseline (ad lib milk), nondairy (soy-based), and dairy diets] separated from the next by 3 weeks. In the chemically tolerant subjects, stably lower beta-endorphin levels suggested that milk may have been a physiologically less stressful beverage than was the soy drink. In contrast, the chemical odor intolerant group exhibited a) increased levels of plasma beta-endorphin averaged over the 6 days (p = .02); and b) marked fluctuations in endorphin from one laboratory day to the next (Group x Diet x Day interaction, p = .005). The findings were consistent with time-dependent, context-dependent sensitization of beta-endorphin in the chemical odor intolerant individuals.