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Psychiatric Morbidity and Toxic Burden in Patients With Environmental Illness: A Controlled Study

From the Department of Toxicology, II. Med. Clinic (S.B., C.H., T.Z.) and the Department of Psychiatry and Psychotherapy (S.B., C.H., H.F.), Technical University of Munich, Munich, Germany; and Siemens AG, Medical Department, Munich, Germany (F.K.).

Address correspondence and reprint requests to Susanne Bornschein, MD, Department of Toxicology, II. Med. Clinic, Technical University of Munich, Ismaninger Str. 22, D-81675 München, Germany. E-mail: s.bornschein{at}lrz.tu-muenchen.de

	ABSTRACT

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Objective: Patients with environmental illness experience a large number of psychological symptoms. The nature of these symptoms and their pathogenesis (toxicogenic versus psychogenic) is controversial. The objective was to (1) characterize the nature of the psychological symptoms according to well-established diagnostic criteria, and (2) to investigate the association between toxicological factors and psychological symptoms.

Methods: Toxic burden, somatic morbidity, and psychiatric morbidity were assessed in 309 outpatients with environmental illness and 59 semiconductor industry workers matched for age and gender. Psychiatric disorders were assessed by a structured psychiatric interview (SCID), and distress was assessed by the Symptom-Checklist-90-Revised (SCL-90-R). Routine and specific laboratory tests in blood and urine samples were used to assess chemical exposures.

Results: Overall psychiatric morbidity was significantly higher in patients than in controls according to SCID (75% versus 24%). Somatoform, mood, and anxiety disorders were significantly more frequent in patients with environmental illness. They also revealed marked stress on the SCL-90-R somatization subscale and scored significantly higher than controls on most of the other subscales. Industry workers from the control group tended to have higher urine metal concentrations than environmental illness patients and similar concentrations of solvents in blood.

Conclusion: Our data extend previous findings of high psychiatric morbidity in patients with environmental illness. They do not support the notion of a direct causal link between chemical exposure and the psychological symptoms.

Key Words: environmental illness • IEI • psychiatric • somatization • chemical exposure

Abbreviations: IEI = idiopathic environmental intolerances; EI = environmental illness; SCID = Structured Clinical Interview for DSM-IV; AG = Aktiengesellschaft (corporation); BAT = Biologischer Arbeitsstoff-Toleranzwert (German occupational threshold limit value); SCL-90-R = Symptom Checklist 90-Revised; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; PSDI = positive symptom distress index.

	INTRODUCTION

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Many individuals report nonspecific, multiorgan system symptoms, which they attribute to low doses of environmental agents tolerated by most people. This has been described as "multiple chemical sensitivity" (MCS) by Cullen (1). In 1996, a World Health Organization expert group (2) suggested the description "idiopathic environmental intolerances" (IEI) in order to avoid unsubstantiated assumptions of etiology. The term environmental illness (EI), which is also used frequently, appears to be more neutral and includes less specific forms of syndromes related to the environment. Several review articles and position statements on IEI are available (3–8).

Several studies found high psychiatric morbidity in patients with EI (9–19). Not all of the studies used standardized and reliable diagnostic procedures, and not all included a control group.

It was our aim to perform a controlled study of outpatients with EI (not only IEI, but also different symptom constellations with a causal attribution to environmental chemicals) and a control group of semiconductor industry workers exposed to metals and solvents in order to (1) characterize the nature of the psychological symptoms according to well-established diagnostic criteria, and (2) investigate the correlation between toxicological factors and psychological symptoms. We deliberately chose a chemically exposed control group because according to the Cullen (1) concept, occupational exposure to chemicals may be a risk factor for the development of multiple physical and psychological symptoms and chemical sensitivity. Based on the toxicological principle of dose-response, which means that the probability and magnitude of toxic effects increases with the (cumulative) dose and duration of exposure (20,21), it is hypothesized that the prevalence of such symptoms and morbidity would be expected to be similar, or even higher, in the occupationally exposed group compared with the EI patients.

	METHODS

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Our studies were approved by the ethics committee of the Technical University of Munich, Klinikum rechts der Isar.

Subjects
Three hundred nine of a total of 311 consecutive patients who consulted our outpatient department for environmental medicine between 1998 and 2000 were included in the study. There was a predominance of women in our patient sample (62% females versus 38% males). The average age was 45 years. Demographic data are listed in Table 1. The patients complained of heterogeneous symptoms that they attributed to the toxic influence of various environmental chemicals (self-defined "EI"). The majority of patients were self-referred, with few referred by their physicians. Inclusion criteria were that patients had to be at least 15 years of age and to have sufficient German language skills. One patient refused participation. One was not able to speak and understand German sufficiently. All patients gave written informed consent.

The control group consisted of 59 semiconductor industry workers working in a clean room at the Siemens AG, Munich, Germany. Control subjects were matched for age and gender and randomly selected from a complete list of clean-room employees at the plant (n = 720). Because of daily exposure to low doses of metals and solvents in the workplace, all clean-room personnel were submitted to regular checkups at the company physicians’ department. Exposure was considered to be limited, however, because appropriate industrial hygiene procedures were followed. Control persons had been working in the clean room for 13.5 years on average (SD 7.3). All of the selected control subjects agreed to take part in the study and gave written informed consent. They were examined at the company on a usual workday so that recent chemical exposure could be assumed.

One patient withdrew her consent to the psychiatric examination. In the remaining 308 patients and 59 control subjects, a full Structured Clinical Interview for DSM-IV (SCID) I and II interview (see below) was completed.

Procedure
Detailed histories were taken for every patient and control subject. Environmental influences and complaints were documented with a standardized environmental questionnaire that is widespread in Germany (22) that assesses a detailed history of chemical exposures, current symptoms, and preexisting diseases. Psychological distress was measured with the symptom checklist (Symptom Checklist 90-Revised, SCL-90-R) (23). We compared the mean t values for all 9 symptom scales and three global scales in patients and controls. The patients’ t values were compared with the normative values of the instrument. The t transformation defines the mean value of the instrument’s standardization sample as 50 and 1 SD as 10. t Values between 60 and 70 indicate emotional stress.

After physical examination, blood and urine samples were collected for routine laboratory testing and biological monitoring of chemicals (where appropriate). Biomonitoring of metals and solvents was performed in all control subjects. In patients, biological monitoring was performed according to the chemicals suspected. Blood or urine solvent and metal concentrations were not tested in all patients but only in those who attributed their complaints to solvents or metals. Metal screening (analysis of more than 30 different metals and trace elements) of urine samples was carried out by mass spectrometry with inductively coupled plasma (ICP-MS) in a certified laboratory (Chemical Institute, Department of Environmental Protection of the City of Stuttgart, Germany). If there was an increase of one or more metals in the screening, this substance was reevaluated. Blood samples were screened for solvents with gas chromatography.

A standardized psychiatric examination was performed on all participants using the German version of the Structured Clinical Interview (SCID I and II) (24,25) for mental (axis I) and personality (axis II) disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (26). The SCID was applied by two trained psychiatrists (S.B. and C.H.).

For statistical analysis, we used the statistics program SPSS version 10.0. Comparisons of proportions of subjects were made by ² test. Differences in continuous variables were compared with the two-sample t test for normally distributed variables and the Mann-Whitney U test for variables with skewed distribution, both two-tailed.

	RESULTS

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Symptoms and Attributions
Three patients did not report complaints but were concerned that they were possibly poisoned by environmental chemicals. Most patients complained of permanent symptoms which were not provoked by an actual toxic exposure but were present all the time (Table 2). Only 6% reported recurrent symptoms associated with specific exposure (as in IEI, for example).

The majority of control subjects did not report any complaints or concerns (63%, n = 37).

The most frequent complaints of patients and control subjects are listed in Figure 1. Many patients suffered from pain syndromes, neurological and psychiatric symptoms. In the control sample, most symptomatic subjects had pain syndromes. Neuropsychiatric symptoms were also reported, but not as frequently as in the patient group.

View larger version (34K): [in this window] [in a new window]   Figure 1. Most frequent complaints in patients (black) and controls (gray).

The chemicals suspected by the patients as probable causes of their complaints are listed in Table 3. Most patients suspected several chemicals.

Chemical Analyses
The results of the biological monitoring of chemicals were classified as follows: slight increase was defined as exceeding the reference range but still being too low to have any toxicological relevance according to current literature and toxicological databases. Moderate increase was defined as clearly exceeding the reference range but still being lower than the German occupational threshold limit value (Biologischer Arbeitsstoff-Toleranzwert = BAT) or, in toxic metals without a BAT value, lower than concentrations known to have clinical toxic effects.

Urine samples of 106 patients (34%) were screened for mercury. In no single case did the urine mercury concentration exceed the reference range of the population (5.0 µg/l) or even reach toxic values. In 82 patients, it was below detectable values (<0.25 µg/l). The average concentration in the remaining 24 patients was 2.9 µg/l.

We found higher metal exposure in the control group than in patients and comparably low solvent exposure in both groups: In 84 patients (27%) a metal survey analysis was performed. Of the 84, 67 patients (80%) had negative results (metal concentrations below detectable values or within the reference or normal range). Fifteen patients (18%) revealed slight increases in metal concentrations. Two patients had moderately increased aluminum levels: 70.0 µg/l and 134.0 µg/l, respectively. Blood samples of 49 patients (16%) were screened for solvents because they had reported recent occupational or private exposure. In 37 of them (75%) solvents were below detection limits. Nine patients had values within the reference range. Two revealed moderately increased concentrations of acetone, 7.0 mg/l and 13.7 mg/l, respectively, which were still below the German occupational threshold limit value (BAT), which is 80 mg/l urine (comparable with blood concentration). One patient had a trichlorethene blood concentration of 60.0 mg/l. In addition, this person had moderately increased acetone (10.0 mg/l) and chloroform (15.0 mg/l) levels. There are no threshold limit values for trichloroethene and chloroform (trichlormethane). Control subjects were screened for metals and solvents according to their occupational exposure situation. Solvents were below detectable values in 56 subjects (95%). The solvent (trichloroethanol, toluene, xylene) values of three subjects were slightly increased. Forty-four control subjects (74%) had overall normal values in the metal survey analysis of urine samples. Nine (15%) revealed moderately increased metal concentrations, and six showed only slight, toxicologically irrelevant increases of cobalt, nickel, beryllium, manganese, and tin. Six had elevated levels of arsenic, which lay between 100 and 341 µg/l (mean value 208.2 µg/l). Four showed increased lithium concentrations between 120 and 311 µg/l. Aluminum was increased in two control subjects, with 56 and 64 µg/l, respectively. One had an elevated concentration of chromium (46 µg/l). The percentage of patients versus controls with slight and moderate increases in the metal survey analysis and the solvent analysis, respectively, are shown in Figures 2 and 3.

View larger version (28K): [in this window] [in a new window]   Figure 2. Results of the metal survey analysis in patients (n = 84) and controls (n = 59) (percentages of subjects with slightly and moderately increased urine metal concentrations).

View larger version (27K): [in this window] [in a new window]   Figure 3. Results of the solvent analysis in patients (n = 49) and controls (n = 59) (percentages of subjects with slightly and moderately increased blood solvent concentrations).

View larger version (35K): [in this window] [in a new window]   Figure 4. Frequency of psychiatric diagnoses in patients (n = 308) and controls (n = 59).

SCL-90-R
The SCL-90-R was completed by 300 patients and all control subjects. As it is demonstrated in Table 4, our patients exceeded the mean value (50) on the scales for obsessive-compulsiveness, social insecurity, depression, anxiety, aggression, phobic anxiety, paranoid ideation, and psychoticism, but they remained within 1 SD. Marked distress (more than 1 SD above mean value) was measured on the somatization scale and the PSDI (positive symptom distress index), which measures the intensity of the answers. Compared with the control group, patients revealed higher values on all scales except psychoticism, where controls scored higher. The differences were significant (p < .05) on all scales except aggression and paranoid ideation.

Concurrent Medical Conditions
Patients demonstrated a variety of somatic diseases, many of which had been diagnosed before, but their cause remained unclear (idiopathic diseases). Examples of somatic disorders are allergy (n = 28), spine diseases (n = 16), polyneuropathy (n = 12), alopecia (n = 10), and multiple sclerosis (n = 4). Other patients presented with a cluster of symptoms that could be brought in line with well-known somatic diseases not diagnosed before, such as hypertension (n = 13) and hyperthyroidism (n = 3). Somatic diseases that accounted for the symptoms in the control sample were spine diseases (n = 5), arthrosis (n = 4), migraine (n = 4), hypotension (n = 2), and hypertension (n = 2), among others.

	DISCUSSION

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Both patients and control subjects reported symptoms that are common in the general population. Patients reported more neuropsychiatric symptoms, whereas controls mainly complained about pain and other physical symptoms. The control subjects tended to have a higher metal body burden than the patients, but both groups were comparable regarding their blood solvent concentrations.

The results confirm previous findings showing high psychiatric morbidity in environmental patients (9–19). Psychiatric morbidity in the control group, however, did not exceed normal rates. Somatoform disorders were the most frequent diagnoses in the patients, followed by mood and anxiety disorders. Patients, in contrast to controls, also revealed marked distress on the somatization subscale and the PSDI of the SCL-90-R.

Whereas chemical exposure appeared more pronounced in the control group, psychiatric morbidity was significantly higher in patients. This discrepancy suggests that occupational low-dose chemical exposure is not a sufficient risk factor for the development of psychiatric, and specifically somatoform, disorders.

One may argue that psychiatric morbidity of patients with EI is overestimated by relabeling the patients’ symptoms as somatoform disorders. However, the proportion of patients with psychiatric diagnoses other than somatoform disorders was still 60% in our sample. In addition, the diagnosis of a somatoform disorder according to SCID (DSM-IV) requires some features besides the physical complaints, namely, significant impairment of functioning and, after appropriate medical assessment, lack of explanation for the reported symptoms or at least for the severity of the complaints.

The overlap between EI and somatoform disorders is striking, which has also been described by other authors (9,10,13,17,19,27). All diagnostic criteria of somatoform disorders as described in DSM-IV and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision can be equally applied to characterize EI: repeated presentation of somatic complaints ("doctor hopping") combined with demands for medical checkups, patients’ conviction that there must be a somatic explanation for their symptoms despite contrary physician statements, and their refusal to discuss a possible psychogenic origin. Comorbidity with other psychiatric disturbances is also common in both groups of disorders. As we report relatively high rates of previous depressive disorders in patients with EI, the same is known in patients with somatoform disorders.

There are some limitations of our study, specifically with regard to psychiatric diagnosis: the diagnostic category of somatoform disorders is descriptive, and it is not possible to derive causality from such a diagnosis. Chemical exposure has been proposed as a risk factor (28) for the development of EI appearing as multiple somatic and psychiatric symptoms, resembling patients with somatoform disorders. One would therefore expect relatively high proportions of subjects with such symptoms in an occupationally exposed sample such as our control group. Our findings do not support this theory. Instead, we found rates comparable to the general population.

However, our results cannot definitely rule out the possibility that chemical exposure may promote neuropsychiatric symptoms and psychiatric disorders only in sensitive individuals and that our control group did not comprise enough chemically sensitive persons because of a selection bias ("healthy worker effect"). At least "secondary" chemical sensitivity (acquired after beginning to work in the clean room) was not observed: an examination of the company physicians’ data revealed that since the opening of the clean room in 1985, there had been no premature pensions or permanent disablements due to intolerance of workplace chemicals among the plant’s clean-room personnel.

To date, this is the largest controlled cross-sectional diagnostic study of patients with EI using standardized methods and a structured psychiatric interview. The control group of subjects occupationally exposed to chemicals allowed testing of this hypothesis: if chemical exposure was a risk factor for developing multiple physical and psychological symptoms and chemical sensitivity, the prevalence of such symptoms and morbidity would be expected to be similar, or even higher, in the occupationally exposed group compared with the EI patients (20,21). The biological monitoring results suggest that control subjects carried higher body burdens of metals and equal solvent levels compared with patients. Although the measured concentrations of chemicals in the control subjects as a group were not seriously increased, the group still represents a homogeneous sample of persons with a regular, 8-hours-per-day, low-dose occupational exposure to metals and solvents. The fact that we did not find more clear increases in chemical concentrations in the control group can be explained by effective industrial safety measures in the plant. Chronic low dose exposure makes the clean-room workers an ideal control group for EI patients.

It may be criticized that our patient population consisted of subjects with self-defined EI. In the absence of a generally accepted case definition of syndromes related to the environment, the only common feature of all these patients is the belief in a causal role of environmental chemicals.

The study design was cross-sectional. A systematic evaluation of the hypothesis that chronic occupational chemical exposure could promote chemical sensitivity would require a longitudinal trial. Therefore, it would be interesting to reevaluate the study sample after 10 years.

The power of our data are somewhat limited by the fact that only subgroups of patients, according to their medical histories, were screened for metals and solvents.

Educational status could be a confounder in this case-control study. However, patient and control group did not differ considerably with respect to their education. Neither does employment status play a role with respect to psychiatric morbidity. Nevertheless, effects of other possible confounders can never be completely ruled out.

In summary, our results do not suggest a direct link between chemical exposure and the high prevalence of certain mental disorders in our study population. Because of the observational design of this study, however, it is not possible to draw conclusions toward causality.

The authors thank Herman Staudenmayer, PhD, for his valuable advice and help with the manuscript.

	NOTES

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The study was supported by a grant from the Bavarian State Ministry for State Development and Environmental Affairs.

DOI:10.1097/01.psy.0000195723.38991.bf

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