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Occupational Medicine Advance Access originally published online on October 17, 2006
Occupational Medicine 2007 57(2):137-140; doi:10.1093/occmed/kql104
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Short Reports

University of Toronto case–control study of multiple chemical sensitivity-3: intra-erythrocytic mineral levels

Cornelia J. Baines1, Gail E. McKeown-Eyssen1,2, Nicole Riley1, Lynn Marshall3 and Vartouhi Jazmaji1

1 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
2 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
3 Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence to: Cornelia J. Baines, Department of Public Health Sciences, University of Toronto, 155 College Street, Toronto, M5T 3M7, Canada. Tel: +1 416 978 7519; fax: +1 416 978 1490; e-mail: cornelia.baines{at}utoronto.ca


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Conflicts of interest
 References
 
Background Multiple chemical sensitivity (MCS) has an estimated American prevalence of 15%, and no consistently abnormal laboratory tests are available to assist in its diagnosis. Some physicians treating MCS patients have observed changes in intra-erythrocytic minerals (IEMs). As co-factors, minerals could influence detoxication of xenobiotics.

Aim To test whether IEM differed comparing MCS cases with controls.

Methods A total of 408 women meeting validated inclusion and exclusion criteria for MCS participated in this case–control study.

Results No statistically significant differences were observed. However, for copper, chromium, magnesium, molybdenum, sulphur and zinc, mean detectable levels were all lower in cases. No dose–response relationships were found.

Conclusion IEM measurements do not appear to provide useful diagnostic markers for MCS.

Keywords      Chemical intolerance; environmental intolerance; hypersensitivity; MCS; minerals


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conflicts of interest
 References
 
Over 15% of American women report a perceived sensitivity to more than one chemical [1]. Clinicians with a special interest in multiple chemical sensitivity (MCS) have suggested that specific mineral deficiencies are consistent with some symptoms and metabolic problems found in MCS: chromium deficiency with sugar craving and hyperglycemia [2], copper with anaemia and fatigue [3], magnesium with fibromyalgia and chronic fatigue syndrome [4], manganese with impaired glucose metabolism [5], molybdenum with altered sulphite metabolism [6], selenium with increased susceptibility to free radical damage [7], sulphur with impaired detoxication [8] and zinc with impaired sense of smell [9] and sugar craving [10].

To evaluate the role of minerals in MCS, intra-erythrocytic mineral (IEM) analysis was undertaken as one component of a case–control study addressing other laboratory investigations in MCS [11,12]. Our MCS case definition is based on previous research revealing that symptoms linked to a low-level exposure and reduced after removal of the exposure together with symptom chronicity differentiated 1337 patients in family medicine practices presumed to have a low risk of MCS, from 1247 in environmental practices presumably at higher risk. A stronger sense of smell than others have also discriminated between the two practices, and in the absence of that symptom, any two of feeling dull or groggy, feeling spacey and difficulty concentrating discriminated [13].


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conflicts of interest
 References
 
Study design, ethics, case definition, exclusion and inclusion criteria and statistical methods have been described [11,12,13]. A total of 408 women age 25–64 years (216 cases, 192 controls) participated.

Fasting morning blood samples were drawn from recumbent participants into heparinized tubes and centrifuged; the buffy coat and plasma were removed. Red cells were washed three times with saline and then frozen. IEM analysis was done by Philip Analytical Services, an internationally accredited environmental laboratory network. Molybdenum and manganese were analysed by graphite furnace, mercury by cold vapour flameless atomic adsorption and remaining metals by inductively coupled plasma atomic emission spectrometry. Nine minerals (chromium, copper, magnesium, manganese, mercury, molybdenum, selenium, sulphur and zinc), hypothesized to be related to MCS (test panel), and another 12 with no prior hypotheses (routine Philip's panel) were measured.

For each mineral, proportions of cases and controls having detectable levels [per cent detectable (PD)] were compared (chi-square tests). Odds ratios for having detectable levels were estimated using logistic regression, with and without adjustment for potential confounders: age, smoking and birth in Canada. Means of detectable levels (MDL) were compared (t-tests with natural logarithm transformations for skewed data). Logistic regression examined the dose–response relationships between mineral levels (tertiles or quartiles) and probability of being a case. Tobit analyses included subjects with levels below the instrument detection limit and accommodated skewed distribution [11,12], yielding ‘mean of all’ (MOA) levels—detectable and undetectable.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conflicts of interest
 References
 
Cases and controls did not differ regarding age, marital status, educational background or daily or passive smoking. Cases were more likely to have been born in Canada (71 versus 52%, P = 0.002) and to report recent nutritional supplement use (65 versus 51%, P = 0.003).

As hypothesized for the test panel (Table 1), PD, MDL, MOA were lower in cases for chromium and molybdenum. MDL were lower in cases for copper, magnesium, sulphur and zinc. However, differences were not statistically significant. Nor were there consistent or significant dose–response relationships before or after adjustment for confounding (Table 2).


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  		Table 1. Case–control comparisons of IEMs: mean levels in nmol/l x 104 (± SD) and odds ratios (ORs) for detectability

 

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  		Table 2. Dose–response relationship for intra-erythrocytic minerals specified a priori (95% CI) in cases and controls with detectable levels

 
Inconsistent with prior hypotheses were manganese, mercury and selenium results; the direction of case–control differences depended on the measure (PD, MDL or MOA). Inconsistencies were not explained by nutritional supplements. The same patterns were seen in users and non-users. No dose–response relationships were observed.

For the routine Philip's panel, only boron yielded significant findings lower in cases than controls. The MOA was lower, 1.37 versus 1.55 nmol/l x 104, P = 0.04, because cases not using nutritional supplements had lower PD: 66 versus 82%, P = 0.02; lower MDL: 1.44 versus 1.59 nmol/l x 104, P = 0.03 and lower MOA: 1.27 versus 1.47 nmol/l x 104, P = 0.001.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conflicts of interest
 References
 
Using a valid and reproducible case definition [13], our findings are consistent with prior hypotheses that cases would have lower levels of chromium, copper, magnesium, molybdenum, sulphur and zinc. Findings for mercury, selenium and manganese levels were inconsistent, although the observed higher manganese levels in cases align with the neurocognitive symptoms of MCS [14]. However, case–control differences were small and neither statistically nor clinically significant. Thus, multiple comparisons have not led to spurious significance for the test panel. Further, dose–response relationships, a major criterion for causality, were not observed, possibly due to prevalent rather than incident cases.

The significantly lower boron levels in cases, not explained by a prior hypothesis, may be a chance finding.

In conclusion, our results reveal no significant association between MCS and the test panel, and so IEM measurements do not appear to be useful objective diagnostic markers for MCS. Further studies could seek a biologic basis for small case–control differences observed in the test panel.


   Conflicts of interest
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflicts of interest
References
 
None declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflicts of interest
 References
 

  1. Kreutzer R, Neutra RR, Lashuay N. (1999) Prevalence of people reporting sensitivities to chemicals in a population-based survey. Am J Epidemiol 150:1–12.[Abstract/Free Full Text]

  2. Anderson RA. (1986) Chromium metabolism and its role in disease processes in man. Clin Physiol Biochem 4:31–41.[ISI][Medline]

  3. Saari JT. (2000) Copper deficiency and cardiovascular disease: role of peroxidation, glycation and nitration. Can J Physiol Pharmacol 78:848–855.[CrossRef][ISI][Medline]

  4. Cox IM, Campbell MJ, Dowson D. (1991) Red blood cell magnesium and chronic fatigue syndrome. Lancet 337:757–760.[CrossRef][ISI][Medline]

  5. Baly DL, Schneiderman JS, Garcia-Welsh AL. (1990) Effect of manganese deficiency on insulin binding, glucose transport and metabolism in rat adipocytes. J Nutr 120:1075–1079.[Abstract/Free Full Text]

  6. Hille R. (2005) Molybdenum-containing hydroxylases. Arch Biochem Biophys 433:107–116.[CrossRef][ISI][Medline]

  7. Rayman MP. (2000) The importance of selenium to human health. Lancet 356:233–241.[CrossRef][ISI][Medline]

  8. McFadden SA. (1996) Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. Toxicology 111:43–65.[CrossRef][ISI][Medline]

  9. Russell RM, Cox ME, Solomons N. (1983) Zinc and the special senses. Ann Intern Med 99:227–239.[ISI][Medline]

  10. Singh RB, Niaz MA, Rastogi SS, Bajaj S, Gaoli Z, Shoumin Z. (1998) Current zinc intake and risk of diabetes and coronary artery disease and factors associated with insulin resistance in rural and urban populations of North India. J Am Coll Nutr 17:564–570.[Abstract/Free Full Text]

  11. Baines CJ, McKeown-Eyssen GE, Riley N, et al. (2004) Case-control study of multiple chemical sensitivity comparing haematology, biochemistry, vitamins and serum volatile organic compound measures. Occup Med (Lond) 54:408–418.

  12. McKeown-Eyssen GE, Baines CJ, Cole DEC, et al. (2004) Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON 2 and MTHFR. Int J Epidemiol 33:1–8.[Free Full Text]

  13. McKeown-Eyssen GE, Baines CJ, Marshall LM, Jazmaji V, Sokoloff ER. (2001) Multiple chemical sensitivity: discriminant validity of case definitions. Arch Environ Health 56:406–412.[ISI][Medline]

  14. Mergler D, Baldwin M, Belanger S, et al. (1999) Manganese neurotoxicity, a continuum of dysfunction: results from a community-based study. Neurotoxicology 20:372–342.


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This Article
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