Skip to main content
SpringerLink
Log in

Idiopathic Environmental Intolerance

Part 1: A Causation Analysis Applying Bradford Hill’s Criteria to the Toxicogenic Theory

  • Review Article
  • Published:
Toxicological Reviews

Abstract

Idiopathic environmental intolerance (IEI) is a descriptor for a phenomenon that has many names including environmental illness, multiple chemical sensitivity and chemical intolerance. Toxicogenic and psychogenic theories have been proposed to explain IEI. This paper presents a causality analysis of the toxicogenic theory using Bradford Hill’s nine criteria (strength, consistency, specificity, temporality, biological gradient, biological plausibility, coherence, experimental intervention and analogy) and an additional criteria (reversibility) and reviews critically the scientific literature on the topic. The results of this analysis indicate that the toxicogenic theory fails all of these criteria. There is no convincing evidence to support the fundamental postulate that IEI has a toxic aetiology; the hypothesised biological processes and mechanisms are implausible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I

Similar content being viewed by others

References

  1. International Programme on Chemical Safety/World Health Organization (IPCS/WHO). Conclusions and recommendations of a workshop on multiple chemical sensitivities (MCS). Regul Toxicol Pharmacol 1996; 24: S188

    Article  Google Scholar 

  2. Cullen MR. The worker with multiple chemical sensitivities: an overview. Occup Med 1987; 2: 655–62

    PubMed  CAS  Google Scholar 

  3. Popper KR. Conjectures and refutations: the growth of scientific knowledge. New York: Harper and Row/Torchbooks, 1968

    Google Scholar 

  4. Lakatos I. Falsification and the methodology of scientific research programmes. In: Lakatos I, Musgrave A, editors. Criticism and the growth of knowledge. Proceedings of the International Colloquium on the Philosophy of Science; 1965; London. Cambridge: Cambridge University Press, 1970: 91–195

    Google Scholar 

  5. Randolph TG. Human ecology and susceptibility to the chemical environment. Springfield (IL): Charles C. Thomas, 1962

    Google Scholar 

  6. Rea WJ. Chemical sensitivity, vol. 1: principles and mechanisms. Boca Raton (FL): Lewis Publishers/CRC Press, 1992

    Google Scholar 

  7. Rea WJ. Chemical Sensitivity, vol. 2: sources of total body load. Boca Raton (FL): Lewis Publishers/CRC Press, 1994

    Google Scholar 

  8. Rea WJ. Chemical Sensitivity, vol. 3: clinical manifestations of pollutant overload. Boca Raton (FL): Lewis Publishers/CRC Press, 1995

    Google Scholar 

  9. Rea WJ. Chemical Sensitivity, vol. 4: tools of diagnosis and methods of treatment. Boca Raton (FL): Lewis Publishers/CRC Press, 1996

    Google Scholar 

  10. Ashford NA, Miller CS. Chemical exposures: low levels and high stakes. 2nd ed. New York: Van Nostrand Reinhold, 1998

    Google Scholar 

  11. Bell IR, Baldwin CM, Fernandez M, et al. Neural sensitization model for multiple markers in multiple chemical sensitivity. Regul Toxicol Pharmacol 1996; 24: S39

    Article  PubMed  CAS  Google Scholar 

  12. Meggs WJ. Neurogenic inflammation and sensitivity to environmental chemicals. Environ Health Perspect 1993; 101: 234–8

    Article  PubMed  CAS  Google Scholar 

  13. American Academy of Allergy Asthma and Immunology. Board of Directors position statement: idiopathic environmental intolerances. J Allergy Clin Immunol 1999; 103: 36–40

    Article  Google Scholar 

  14. American College of Occupational and Environmental Medicine. Multiple chemical sensitivities: idiopathic environmental intolerance. Position statement. ACOEM Report 1999 Jun: 1–3

  15. American Medical Association. Council on Scientific Affairs Report: clinical ecology. JAMA 1992; 268(24): 3465–7

    Article  Google Scholar 

  16. American College of Physicians. Position paper: clinical ecology. Ann Intern Med 1989; 111: 168–78

    Google Scholar 

  17. Royal College of Physicians. Allergy, conventional and alternative concepts. Report by the Committee on Clinical Immunology and Allergy. London: Royal College of Physicians, 1992

    Google Scholar 

  18. International Society of Regulatory Toxicology and Pharmacology (ISRTP). Report of the Board. Regul Toxicol Pharmacol 1993; 18: 79

    Article  Google Scholar 

  19. American Academy of Clinical Toxicology. Board of Trustees minutes, 2000 Mar 29

  20. Staudenmayer H, Binkley KE, Leznoff A, et al. Idiopathic environmental intolerance: part 2 — a causation analysis applying Bradford Hill’s criteria to the psychogenic theory. Toxicol Rev 2003; 22(3): 247–61

    Article  PubMed  CAS  Google Scholar 

  21. Hill AB. The environment and disease: association or causation. Proc R Soc Med 1965; 58: 295–300

    PubMed  CAS  Google Scholar 

  22. Agency for Toxic Substances and Disease Registry (ATSDR). A quick guide to evaluating environmental exposures. Centers for Disease Control and Prevention. DKH 01-0391. Atlanta (GA): ATSDR, 2001 Oct, 65

    Google Scholar 

  23. Hausteiner C, Bornschein S, Bickel H, et al. Psychiatric morbidity and low selfattentiveness in patients with environmental illness. J Nerv Ment Dis 2003; 191: 50–5

    Article  PubMed  Google Scholar 

  24. Waddell WJ. The science of toxicology and its relevance to MCS. Regul Toxicol Pharmacol 1993; 18: 13–22

    Article  PubMed  CAS  Google Scholar 

  25. National Research Council. Board of Environmental Studies and Toxicology. Workshop on Health Risks from Exposure to Common Indoor Household Products in Allergic or Chemically Diseased Persons; 1987 Jul 1; Washington, DC

    Google Scholar 

  26. Bell IR, Hardin EE, Baldwin CM, et al. Increased limbic system symptomatology and sensitizability of young adults with chemical and noise sensitivities. Environ Res 1995; 70: 84–97

    Article  PubMed  CAS  Google Scholar 

  27. Bell IR. Clinically relevant EEG studies and psychophysiological findings: possible neural mechanisms for multiple chemical sensitivity. Toxicology 1996; 111: 101–17

    Article  PubMed  CAS  Google Scholar 

  28. Meggs WJ, Dunn KA, Bloch RM, et al. Prevalence and nature of allergy and chemical sensitivity in a general population. Arch Environ Health 1996; 51: 275–82

    Article  PubMed  CAS  Google Scholar 

  29. Ross PM, Whysner J, Covello VT, et al. Olfaction and symptoms in multiple chemical sensitivities syndrome. Prev Med 1999; 28: 467–80

    Article  PubMed  CAS  Google Scholar 

  30. Kreutzer R, Neutra RR, Lashuay N. Prevalence of people reporting sensitivities to chemicals in a population based survey. Am J Epidemiol 1999; 150: 1–12

    Article  PubMed  CAS  Google Scholar 

  31. Young E, Stoneham MD, Petruckevitch A, et al. A population study of food intolerance. Lancet 1994; 343: 1127–30

    Article  PubMed  CAS  Google Scholar 

  32. Young E, Patel S, Stoneham M, et al. The prevalence of reaction to food additives in a survey population. J R Coll Physicians Lond 1987; 21: 241–7

    PubMed  CAS  Google Scholar 

  33. Niestijl-Jansen JJ, Kardinaal AFM, Huijbers G, et al. Prevalence of food allergy and intolerance in the adult Dutch population. J Allergy Clin Immunol 1994; 93: 446–56

    Article  Google Scholar 

  34. Selner JC. Chamber challenges: the necessity of objective observation. Reg Toxicol Pharmacol 1996; 24: S87

    Article  CAS  Google Scholar 

  35. McCourtie D. An overview. In: Chronic diseases in Canada: Environmental Sensitivities Workshop. Ottawa: Health Protection Branch, Health and Welfare Canada, 1990 May 24

    Google Scholar 

  36. Rea WJ, Ross GH, Johnson AR, et al. Confirmation of chemical sensitivity by means of double-blind inhalant challenge of toxic volatile chemicals. Clin Ecology 1990; 6: 113–8

    Google Scholar 

  37. Jewett DL. Research strategies for investigating multiple chemical sensitivity. Toxicol Ind Health 1992; 8: 175–9

    PubMed  CAS  Google Scholar 

  38. Kilburn KH. Chemical brain injury. New York: Van Norstrand Reinhold, 1998

    Google Scholar 

  39. Sullivan Jr JB, Krieger GR. Hazardous materials toxicology: clinical principles of environmental health. Baltimore (MD): Williams & Wilkins, 1992

    Google Scholar 

  40. Schaumburg HH, Spencer PS, Ludolph AC, editors. Experimental and clinical neurotoxicology. 2nd ed. New York: Oxford University Press, 2000

    Google Scholar 

  41. Simon GE, Daniell W, Stockbridge H, et al. Immunologic, psychological and neuropsychological factors in multiple chemical sensitivity. Ann Intern Med 1993; 19: 97–103

    Google Scholar 

  42. Bolla KI. Neurobehavioral performance in multiple chemical sensitivities. Reg Toxicol Pharmacol 1996; 24: S52

    Article  CAS  Google Scholar 

  43. Fiedler N, Kipen HM, Deluca J, et al. A controlled comparison of multiple chemical sensitivities and chronic fatigue syndrome. Psychosom Med 1996; 58: 38–49

    PubMed  CAS  Google Scholar 

  44. Brown-DeGagne AM, McGlone J. Multiple chemical sensitivity: a test of the olfactory-limbic model. J Occup Environ Med 1999; 41: 366–77

    Article  PubMed  CAS  Google Scholar 

  45. Bolla KI. Use of neuropsychological testing in idiopathic environmental testing. Occup Med 2000; 15: 617–25

    PubMed  CAS  Google Scholar 

  46. American Academy of Neurology. Report of the Therapeutics and Technology Assessment Subcommittee. Assessment: neuropsychological testing in adults. Neurology 1996; 47: 592–9

    Article  Google Scholar 

  47. Benton AL. Neuropsychological assessment. Annu Rev Psychol 1994; 45: 1–23

    Article  PubMed  CAS  Google Scholar 

  48. Matarazzo JD. Psychological assessment versus psychological testing: validation from the Binet to the school, clinic and courtroom. Am Psychol 1990; 45: 999–1017

    Article  PubMed  CAS  Google Scholar 

  49. White RF, Proctor SP. Research and clinical criteria for development of neurobehavioral test batteries. J Occup Med 1991; 34: 140–8

    Article  Google Scholar 

  50. Mayberg H. Critique: SPECT studies of multiple chemical sensitivity. Toxicol Ind Health 1994; 10: 661–6

    PubMed  CAS  Google Scholar 

  51. Moser F, Schaeffer J, Waxman AD, et al. New modalities of brain imaging and neurocognitive assessment: emerging areas of interest and controversy related to applications in head injury, neurotoxicology and environmental medicine. Disability 1995; 4: 1–12

    Google Scholar 

  52. Society of Nuclear Brain Imaging Council. Ethical clinical practice of functional brain imaging. J Nucl Med 1996; 37: 1256–9

    Google Scholar 

  53. Callender TJ, Morrow L, Subramanian K, et al. Three-dimensional brain metabolic imaging in patients with toxic encephalopathy. Environ Res 1993; 60: 296–319

    Article  Google Scholar 

  54. Heuser G, Mena I, Goldstein J, et al. Neurospect findings in patients exposed to neurotoxic chemicals [abstract]. Clin Nucl Med 1993; 18: 923

    Article  Google Scholar 

  55. Fincher CE, Chang T, Harrell EH, et al. Comparison of single photon emission computed tomography findings in cases of healthy adults and solvent-exposed adults. Am J Ind Med 1997; 31: 4–14

    Article  PubMed  CAS  Google Scholar 

  56. Frazblau A, Minoshima S, Robins TG, et al. Letter to the Editor. Am J Ind Med 1997; 32: 695–7

    Article  Google Scholar 

  57. Fincher CE, Chang T, Harrell EH, et al. Letter to the Editor. Am J Ind Med 1997; 32: 698–701

    Article  Google Scholar 

  58. Wolfe J, Charney DS. Use of neuropsychological assessment in posttraumatic stress disorder. Psychol Assess 1991; 3: 573–80

    Article  Google Scholar 

  59. Golier JA, Yehuda R, Lupien SJ. Memory performance in holocaust survivors with posttraumatic stress disorder. Am J Psychiatry 2002; 159: 1682–8

    Article  PubMed  Google Scholar 

  60. Cohen RA, O’Donnell BF. Attentional dysfunction associated with psychiatric illness. In: Cohen RA, editor. The neuropsychology of attention. New York: Plenum, 1993: 275–306

    Google Scholar 

  61. Bemelmans KJ, Goekoop JG, van Kempen GM. Recall performance in acutely depressed patients and plasma cortisol. Biol Psychiatry 1996; 39: 750–2

    Article  PubMed  CAS  Google Scholar 

  62. Rubinow DR, Post RM, Savard R, et al. Cortisol hypersecretion and cognitive impairment in depression. Arch Gen Psychiatry 1984; 41: 279–83

    Article  PubMed  CAS  Google Scholar 

  63. Leznoff A. Provocative challenges in patients with multiple chemical sensitivity. J Allergy Clin Immunol 1997; 99: 438–42

    Article  PubMed  CAS  Google Scholar 

  64. Bell IR. Clinical ecology: a new medical approach to environmental illness. Bolinas (CA): Common Knowledge Press, 1982

    Google Scholar 

  65. Terr AI. Unconventional theories and unproven methods in allergy. In: Middleton Jr E, Reed CE, Ellis EF, et al., editors. Allergy: principles and practice. 4th ed. St Louis (MO): Mosby,. 1993; 2: 1767–93

    Google Scholar 

  66. Miller CS. Toxicant-induced loss of tolerance: an emerging theory of disease? Environ Health Perspect 1997; 105Suppl. 2: 445–53

    PubMed  Google Scholar 

  67. Bell IR, Schwartz GE, Amend D, et al. Sensitization to early life stress and responses to chemical odors in older adults. Biol Psychiatry 1994; 35: 857–63

    Article  PubMed  CAS  Google Scholar 

  68. Kagan J, Reznick JS, Snidman N. Biological bases of childhood shyness. Science 1988; 240: 167–71

    Article  PubMed  CAS  Google Scholar 

  69. Bell IR. Neuropsychiatric aspects of sensitivity to low-level chemicals: a neural sensitization model. Toxicol Ind Health 1994; 10: 277–312

    PubMed  CAS  Google Scholar 

  70. Young EA, Carlson NE, Brown MB. Twenty-four hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology 2001; 25: 267–76

    Article  PubMed  CAS  Google Scholar 

  71. Heim C, Newport DH, Heit S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 2000; 284: 592–7

    Article  PubMed  CAS  Google Scholar 

  72. Staudenmayer H, Selner ME, Selner JC. Adult sequelae of childhood abuse presenting as environmental illness. Ann Allergy 1993; 71: 538–46

    PubMed  CAS  Google Scholar 

  73. Brodsky CM. ‘Allergic to everything’: a medical subculture. Psychosomatics 1983; 24: 731–42

    Article  PubMed  CAS  Google Scholar 

  74. Selner JC, Staudenmayer H. The relationship of the environment and food to allergic and psychiatric illness. In: Young SH, Rubin JM, Daman HR, editors. Psychophysiological aspects of allergic disorders. New York: Praeger, 1986: 102–46

    Google Scholar 

  75. Black DW. Iatrogenic (physician-induced) hypochondriasis: four patient examples of ‘chemical sensitivity.’ Psychosomatics 1996; 37: 390–3

    Article  PubMed  CAS  Google Scholar 

  76. Hodgson MJ, Frohliger J, Permar E, et al. Symptoms and microenvironmental measures in non-problem buildings. J Occup Med 1991; 33: 527–33

    PubMed  CAS  Google Scholar 

  77. Hodgson MJ. Indoor environmental exposures and symptoms. Environ Health Perspect 2002; 110Suppl. 4: 663–7

    Article  PubMed  CAS  Google Scholar 

  78. Staudenmayer H. Environmental illness: myth and reality. Boca Raton: CRC/Lewis Publishers, 1999

    Google Scholar 

  79. Selner JC. Book review of chemical exposures, low levels and high stakes by Ashford N and Miller CS. Ann Allergy 1991; 67: 456

    Google Scholar 

  80. Viaene MK, Masschelein R, Leenders J, et al. Neurobehavioral effects of occupational exposure to cadmium: a cross sectional epidemiological study. Occup Environ Health 2000; 57: 19–27

    CAS  Google Scholar 

  81. Rea WJ, Bell IR, Suits CW, et al. Food and chemical susceptibility after environmental chemical overexposure: case histories. Ann Allergy 1978; 41: 101–10

    PubMed  CAS  Google Scholar 

  82. Levin AS, Byers VS. Environmental illness: a disorder of immune regulation. Occup Med 1987; 2: 669–81

    PubMed  CAS  Google Scholar 

  83. Bascom R. Multiple chemical sensitivity: a respiratory disorder? Toxicol Ind Health 1992; 8: 221–8

    PubMed  CAS  Google Scholar 

  84. Rosenberg NL, editor. Occupational and environmental neurology. Newton (MA): Butterworth-Heineman, 1995

    Google Scholar 

  85. Altenkirch H, Hopmann D, Brockmeier B, et al. Neurological investigations in 23 cases of pyrethroid intoxication reported to the German Federal Health Office. Neurotoxicology 1996; 17: 645–52

    PubMed  CAS  Google Scholar 

  86. Waxman AD. Functional brain imaging in the assessment of multiple chemical sensitivity. Occup Med 2000; 15: 611–6

    PubMed  CAS  Google Scholar 

  87. Staudenmayer H, Kramer RE. Psychogenic chemical sensitivity: psychogenic pseudoseizures elicited by provocation challenges with fragrances. J Psychosom Res 1999; 47: 185–90

    Article  PubMed  CAS  Google Scholar 

  88. Dager SR, Marro KI, Richards TL, et al. Preliminary application of magnetic resonance spectroscopy to investigate lactate-induced panic. Am J Psychiatry 1994; 151: 57–63

    PubMed  CAS  Google Scholar 

  89. Dager SR, Strauss WL, Marro KI, et al. Proton magnetic resonance spectroscopy investigation of hyperventilation in subjects with panic disorder and comparison subjects. Am J Psychiatry 1995; 152: 666–72

    PubMed  CAS  Google Scholar 

  90. Binkley KE, Kutcher S. Panic response to sodium lactate infusion in patients with multiple chemical sensitivity syndrome. J Allergy Clin Immunol 1997; 99: 570–4

    Article  PubMed  CAS  Google Scholar 

  91. Poonai N, Anthony MM, Binkley KE, et al. Carbon dioxide inhalation challenges in idiopathic environmental intolerance. J Allergy Clin Immunol 2000; 105: 358–63

    Article  PubMed  CAS  Google Scholar 

  92. Binkley K, King N, Poonai N, et al. Idiopathic environmental intolerance: increased prevalence of panic disorder-associated cholecystokinin B receptor allele 7. J Allergy Clin Immunol 2001; 107: 887–90

    Article  PubMed  CAS  Google Scholar 

  93. Bell IR, Miller CS, Schwartz GE. An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders. Biol Psychiatry 1992; 32: 218–42

    Article  PubMed  CAS  Google Scholar 

  94. Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 1969; 25: 295–330

    Article  PubMed  CAS  Google Scholar 

  95. Racine R. Kindling: the first decade. Neurosurgery 1978; 3: 234–52

    Article  PubMed  CAS  Google Scholar 

  96. Wada JA. Kindling 4. New York: Plenum, 1990

    Google Scholar 

  97. Bell IR, Schwartz GE, Peterson JM, et al. Possible time-dependent sensitization to xenobiotics: self-reported illness from chemical odors, foods, and opiate drugs in an older adult population. Arch Environ Health 1993; 48: 315–27

    Article  PubMed  CAS  Google Scholar 

  98. Antelman SM. What are the implications of drug-induced time-dependent sensitization?: conclusions. Drug Dev Res 1988; 14: 1–30

    Article  CAS  Google Scholar 

  99. Antelman SM, Kocan D, Edwards DJ, et al. A single injection of diazepam induces long-lasting sensitization. Psychopharmacol Bull 1987; 23: 430–4

    PubMed  CAS  Google Scholar 

  100. Post RM, Weiss SRB, Smith M, et al. Stress, conditioning, and the temporal aspect of affective disorders. Ann N Y Acad Sci 1995; 771: 677–96

    Article  PubMed  CAS  Google Scholar 

  101. Yehuda R, Antelman SM. Criteria for rationally evaluating animal models of posttraumatic stress disorder. Biol Psychiatry 1993; 33: 479–86

    Article  PubMed  CAS  Google Scholar 

  102. Post RM, Weiss SRB, Pert A. Cocaine-induced behavioral sensitization and kindling: implications for the emergence of psychopathology and seizures. Ann N Y Acad Sci 1988; 537: 292–308

    Article  PubMed  CAS  Google Scholar 

  103. Bell IR, Schwartz GE, Baldwin CM, et al. Neural sensitization and physiological chemical sensitivity: overview of theory and empirical evidence. Toxicol Ind Health 1999; 15: 295–307

    PubMed  CAS  Google Scholar 

  104. Kurt TL. Multiple chemical sensitivities: a syndrome of pseudotoxicity manifest as exposure perceived symptoms. Clin Toxicol 1995; 33: 101–5

    Article  CAS  Google Scholar 

  105. Ross GH. Treatment options in multiple chemical sensitivity. Toxicol Ind Health 1992; 8: 87–94

    PubMed  CAS  Google Scholar 

  106. Jewett DL, Fein G, Greenberg MH. A double-blind study of symptom provocation to determine food sensitivity. N Engl J Med 1990; 323: 429–33

    Article  PubMed  CAS  Google Scholar 

  107. Staudenmayer H. Clinical consequences of the EI/MCS ‘diagnosis’: two paths. Regul Toxicol Pharmacol 1996; 24: S96–S110

    Article  PubMed  CAS  Google Scholar 

  108. Ames BN, Gold LS. The causes and prevention of cancer: the role of the environment. In: Bailey R, editor. The true state of the planet. New York: Free Press, 1995: 141–75

    Google Scholar 

Download references

Acknowledgements

No funding was received to assist the preparation of this manuscript. The authors have no conflict of interest. We thank Su Dierbeck for secretarial assistance. We dedicate this work to the memory of our colleague, Neil L. Rosenberg, M.D.

Author information

Authors and Affiliations

  1. Behavioral Medicine, Multi-Disciplinary Toxicology, Treatment and Research Center, 5800 E. Evans Ave, Suite 20B, Denver, Colorado, 80222, USA

    Herman Staudenmayer

  2. Division of Clinical Immunology and Allergy, University of Toronto, Toronto, Canada

    Karen E. Binkley & Arthur Leznoff

  3. Toxicology Associates, Multi-Disciplinary Toxicology, Treatment and Research Center, Denver, Colorado, USA

    Scott Phillips

Authors
  1. Herman Staudenmayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen E. Binkley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arthur Leznoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott Phillips
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Herman Staudenmayer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staudenmayer, H., Binkley, K.E., Leznoff, A. et al. Idiopathic Environmental Intolerance. Toxicol Rev 22, 235–246 (2003). https://doi.org/10.2165/00139709-200322040-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00139709-200322040-00005

Keywords

Search

Navigation